Post on 04-Apr-2015
Polymorphism of Human Cytochrome P450 2D6and Its Clinical SignificancePart II
Shu-Feng Zhou
School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
1. Clinical Genotype-Phenotype Relationships of Human Cytochrome P450 2D6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
1.1 Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
1.1.1 Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
1.1.2 Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
1.1.3 Other Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
1.1.4 Summary of Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
1.2 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
1.2.1 Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
1.2.2 Chlorpromazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
1.2.3 Haloperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
1.2.4 Perphenazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
1.2.5 Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
1.2.6 Thioridazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
1.2.7 Zuclopenthixol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
1.2.8 Miscellaneous Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
1.2.9 Summary of Antipsychotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
1.3 Centrally Acting Cholinesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
1.3.1 Donepezil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
1.3.2 Galantamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780
1.4 Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780
1.4.1 Atomoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780
1.5 Drugs for the Treatment of Senile Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
1.5.1 Nicergoline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
1.6 Antimuscarinic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
1.6.1 Tolterodine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
1.7 Antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
1.7.1 Dolasetron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
1.7.2 Ondansetron. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
1.7.3 Tropisetron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
1.7.4 Summary of Antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
1.8 Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
1.8.1 Chlorpheniramine (Chlorphenamine). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
1.8.2 Diphenhydramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
1.8.3 Loratadine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
1.8.4 Summary of Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
1.9 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
REVIEW ARTICLEClin Pharmacokinet 2009; 48 (12): 761-804
0312-5963/09/0012-0761/$49.95/0
ª 2009 Adis Data Information BV. All rights reserved.
1.9.1 Codeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
1.9.2 Dihydrocodeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
1.9.3 Hydrocodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
1.9.4 Oxycodone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
1.9.5 Methadone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
1.9.6 Tramadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
1.9.7 Summary of Opioids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
1.10 Oral Antihyperglycaemic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
1.10.1 Phenformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
1.11 Selective Estrogen Receptor Modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
1.11.1 Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
2. Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
Abstract Part I of this article discussed the potential functional importance of genetic mutations and alleles of the
human cytochrome P450 2D6 (CYP2D6) gene. The impact of CYP2D6 polymorphisms on the clearance of
and response to a series of cardiovascular drugs was addressed. Since CYP2D6 plays a major role in the
metabolism of a large number of other drugs, Part II of the article highlights the impact of CYP2D6
polymorphisms on the response to other groups of clinically used drugs.
Although clinical studies have observed a gene-dose effect for some tricyclic antidepressants, it is difficult
to establish clear relationships of their pharmacokinetics and pharmacodynamic parameters to genetic
variations of CYP2D6; therefore, dosage adjustment based on the CYP2D6 phenotype cannot be
recommended at present. There is initial evidence for a gene-dose effect on commonly used selective
serotonin reuptake inhibitors (SSRIs), but data on the effect of the CYP2D6 genotype/phenotype on the
response to SSRIs and their adverse effects are scanty. Therefore, recommendations for dose adjustment of
prescribed SSRIs based on the CYP2D6 genotype/phenotype may be premature.
A number of clinical studies have indicated that there are significant relationships between the CYP2D6
genotype and steady-state concentrations of perphenazine, zuclopenthixol, risperidone and haloperidol.
However, findings on the relationships between the CYP2D6 genotype and parkinsonism or tardive dys-
kinesia treatment with traditional antipsychotics are conflicting, probably because of small sample size,
inclusion of antipsychotics with variable CYP2D6 metabolism, and co-medication. CYP2D6 phenotyping
and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic
drugs, but their usefulness in predicting clinical effects must be explored. Therapeutic drug monitoring has
been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine,
perphenazine, risperidone and thioridazine, which are all metabolized by CYP2D6. It is possible to merge
therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice.
There is a clear gene-dose effect on the formation of O-demethylated metabolites from multiple opioids,
but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers
(PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine
formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyl-
tramadol and reduces the clearance of methadone. Genetically precipitated drug interactions might render a
standard opioid dose toxic.
Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to
exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and
toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen.
Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly de-
creased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and
shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent
predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed
this relationship. Thus, more favourable tamoxifen treatment seems to be feasible through a priori genetic
762 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is de-
termined in a patient.
Dolasetron, ondansetron and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs
than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron.
CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing.
An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron,
which would obviate the need for genotyping and may lead to an improved drug response.
To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most
clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been
identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on
CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs.
Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that genotype
testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding
genotype-phenotype, gene-concentration and gene-dose relationships, further prospective studies on the
clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts.
Part I of this article, which appeared in the last issue of
Clinical Pharmacokinetics,[1] discussed the human cytochrome
P450 (CYP) 2D locus, substrates of human CYP2D6, genetic
mutations of human CYP2D6 and their impact on enzyme ac-
tivity, and clinical genotype-phenotype relationships of human
CYP2D6 with respect to antianginal drugs, antiarrhythmic drugs
and b-adrenoceptor antagonists.
1. Clinical Genotype-Phenotype Relationships of
Human Cytochrome P450 2D6
1.1 Antidepressants
1.1.1 Tricyclic Antidepressants
Most tricyclic antidepressants have a low to moderate
therapeutic index; they give rise to remarkable adverse effects at
therapeutic concentrations and are dangerous when patients
are overdosed. These agents are high-clearance drugs that un-
dergo extensive phase I and phase II metabolism.[2] They exist
as tertiary or secondary amines, and the tertiary forms are
metabolized to secondary amines. Both the tertiary and sec-
ondary amines are active, as are some of the resultant hydro-
xylated metabolites. The tertiary amines are metabolized by
multiple CYP isoenzymes (mainly CYP2C19 and 2C9), while
the secondary amines are largely metabolized by CYP2D6.[2]
Amitriptyline and Nortriptyline
Both amitriptyline and nortriptyline are indicated for the
treatment of depression.[3] CYP2D6 is responsible for the
conversion of amitriptyline and nortriptyline to E-10-hydroxy-
amitriptyline and E-10-hydroxynortriptyline via benzylic hy-
droxylation, respectively, whereas demethylation of ami-
triptyline to nortriptyline and of E-10-hydroxyamitriptyline to
E-10-hydroxynortriptyline is mainly catalysed by CYP2C19,
2C9, 1A2 and 3A4 (see supplementary figure 15, Supplemental
Digital Content 1, http://links.adisonline.com/CPZ/A8).[4-7] The
metabolism of nortriptyline is simpler than that of amitriptyline
and is largely by CYP2D6 (>80% in extensive metabolizers
[EMs]).[8] The hydroxylation of nortriptyline by CYP2D6 is
highly stereoselective, mainly forming R-E-10-hydroxynortripty-
line.[9,10] E-10-hydroxynortriptyline is active, with approximately
half the potency of the parent drug in inhibiting norepinephrine
(noradrenaline) reuptake and greatly decreased anticholinergic
activity.[11] A significant correlation between amitriptyline
clearance and the debrisoquine metabolic ratio (MR) has been
found in nonsmokers.[12] A significant correlation between
total clearance of nortriptyline via E-10 hydroxylation and
the activity of CYP2D6 as determined by debrisoquine hy-
droxylation or sparteine oxidation has also been observed.[13-15]
After giving a 25mg dose of nortriptyline to 21 healthy Swedish
Caucasians, the mean area under the plasma concentration-
time curve (AUC) values of nortriptyline in poor metabolizers
(PMs) harbouring CYP2D6*4/*4 were 3.3-fold higher than
those observed in EMs, with opposite changes in plasma
10-hydroxynortriptyline concentrations and lower concentrations
in PMs.[16] The plasma concentrations of the parent drug were ex-
tremely low in one subject with 13CYP2D6*2 genes, but very highconcentrations of 10-hydroxynortriptyline were noted.[16] This
study clearly demonstrated the clinical impact of thenonfunctional
CYP2D6*4 allele aswell as that of the duplication/amplification of
the CYP2D6*2 gene on the disposition of nortriptyline.
There was a significant correlation between the CYP2D6
genotype and steady-state plasma concentrations of nortriptyline
Pharmacogenetics of CYP2D6 763
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
in Swedish patients with depression receiving nortriptyline
therapy.[13] Similar changes in the AUC have also been ob-
served in individuals carrying defectiveCYP2D6 alleles leading
to reduced activity (e.g. CYP2D6*10) in Chinese healthy sub-
jects[17] and Japanese patients with depression,[18] but the effect
was less pronounced than that of the Caucasian-specific
CYP2D6*4 allele. These two studies clearly demonstrated
the influence of the CYP2D6*10 allele on the steady-state
plasma concentrations of nortriptyline and its 10-hydroxy
metabolite. However, a recent study in Faroese patients
reported similar plasma concentrations of amitriptyline and
10-hydroxynortriptyline in PMs and EMs.[19]
Owing to significantly reduced CYP2D6-mediated meta-
bolism, PMs have higher plasma concentrations of tricyclic
antidepressants metabolized by CYP2D6 than EMs and are
therefore more likely to experience dose-dependent adverse
drug reactions. Patients carrying one dysfunctional CYP2D6
allele had a greater risk of adverse effects with amitriptyline
150mg daily than those with two functional alleles (76.5% vs
12.1%), and this risk was associated with higher plasma nor-
triptyline concentrations.[20] However, another study in pa-
tients with depression did not find a significant effect of
CYP2D6 mutations on the incidence of adverse reactions
caused by nortriptyline.[21] Since the major metabolites of
nortriptyline are active, altered parent/metabolite ratios due
to the presence of nonfunctional CYP2D6 alleles would not
significantly alter the sum of the active moieties.
A number of cases have been reported in which marked CNS
toxicities (e.g. dizziness and sedation)with increasednortriptyline
plasma concentrations in PMs and individuals receiving
CYP2D6 inhibitors such as terbinafine were documented.[22]
Cases of therapeutic failures in ultrarapidmetabolizers (UMs) on
nortriptyline have also been documented.[23] However, the
anticholinergic effects, including inhibition of salivation, accom-
modation disturbances, sedation and effects on the blood pres-
sure and pulse rate, did not differ between genotypes in healthy
subjects receiving a single dose of nortriptyline (25–50mg).[16]
Clomipramine
Clomipramine, a tricyclic antidepressant, is a potent inhibitor
of serotonin (5-HT) reuptake and may affect dopaminergic
neurotransmission.[24] Clomipramine is well absorbed from the
gastrointestinal tract but undergoes important first-pass meta-
bolism toN-demethylclomipramine (norclomipramine), which is
pharmacologically active and participates in both therapeutic
and unwanted effects.[25] Clomipramine is converted to active
N-desmethylclomipramine by CYP2C19, 1A2 and 3A4, and
both compounds are metabolized to respective hydroxylated
metabolites with hydroxylation at positions 2, 8 and 10 of the
benzyl rings, largely by CYP2D6 (see supplementary figure 16,
Supplemental Digital Content 1).[26] Clomipramine is also con-
verted to the 2- or 10-hydroxylated metabolite, which is further
N-demethylated. These oxidative metabolites can be further
conjugated by glucuronidation.
The plasma AUC of clomipramine after a single dose of
100mg has been shown to be ~1.8-fold higher in PMs than in
EMs.[27] The formation clearance of 2-hydroxyclomipramine and
total clearance of clomipramine were significantly lower in PMs
than in EMs. In a steady-state study of 37 patients with depres-
sion, comprising 36 EMs and 1 PM (sparteine MR >300) whoreceived clomipramine 75mg twice daily, the sole PMhad trough
plasma concentrations of clomipramine, N-desmethylclomipra-
mine and the sum of clomipramine plus N-desmethylclomipra-
mine that were ~3-fold higher than the median concentrations
of the respective compound in EMs.[28] The clomipramine
concentration was within the range seen in EMs (570 in the PM
vs 70–730nmol/L in the EMs), whereas the desmethylclomipra-
mine and summed concentrations were 20–40% above the upper
concentrations in EMs.[28] The PM had the highest steady-state
plasma desmethylclomipramine concentration and the highest
desmethylclomipramine/8-hydroxydesmethylclomipramine ratio.
The desmethylclomipramine and didesmethylclomipramine
steady-state concentrations and the desmethylclomipramine/8-hydroxydesmethylclomipramine and clomipramine/8-hydroxy-clomipramine ratios showed a significant positive correlation
with the MR. However, the steady-state plasma clomipramine
concentrations and the clomipramine/desmethylclomipramine
ratios showed no significant correlation with the MR.
In another steady-state study in 19 patients with diabetic
neuropathy who received a lower dose of clomipramine
(50mg/day), the summed concentrations of clomipramine and
desmethylclomipramine were markedly higher in two PMs (590
and 750 nmol/L) than in EMs (70–510 nmol/L).[29] Patients witha weak or absent response to clomipramine had lower plasma
concentrations of clomipramine plus desmethylclomipramine
(<200 nmol/L) than patients with a better response. It appeared
that there was no difference in the incidence of adverse effects
between PMs and EMs. These results indicate that proper dose
adjustment based on the CYP2D6 phenotype can assist in at-
taining target concentrations of clomipramine.
Doxepin
Doxepin, a tricyclic antidepressant with a structure similar
to those of cyclobenzaprine, amitriptyline, imipramine and
protriptyline, inhibits the reuptake of serotonin and nor-
epinephrine from the synaptic cleft.[30] Doxepin is given as a
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15 : 85 mixture of Z-cis-/E-trans-isomers, with Z-cis-doxepin
being considered to have greater antidepressive effect. Doxepin is
extensively metabolized in the liver, and its phase I and phase II
metabolites have been identified in human plasma, urine and
cerebrospinal fluid.[31] The urinary metabolites in humans are
(E)-2-hydroxydoxepin, (E)-2-hydroxy-N-desmethyldoxepin, (Z)-
and (E)-N-desmethyldoxepin, (Z)- and (E)-doxepin-N-oxide,
(E)-2-O-glucuronyldoxepin and a quaternary ammonium-linked
glucuronide.[31] The N+-glucuronide is a major metabolite in
patient urine after doxepin administration. CYP2D6mainly con-
verts the E-isomer of doxepin to its active metabolite, 2-hydroxy
derivative, while the formation of N-desmethyldoxepin (nor-
doxepin) is mainly catalysed by CYP2C19 and 3A4 (see supple-
mentary figure 17, Supplemental Digital Content 1).[32-34]
The AUC of the active moieties after a single oral dose of
75mg has been shown to be ~3-fold higher in PMs than in EMs,
whereas intermediate metabolizers (IMs) behaved similarly to
EMs.[34] The median AUC values of the active metabolite
desmethyldoxepin were 5.28, 1.35 and 1.28 nmol � h/L in PMs,
IMs and EMs of substrates of CYP2D6, respectively. Mean E-
doxepin clearance was 406, 247 and 127L/h in EMs, IMs and
PMs.[34] In addition, EMs had about 2-fold lower bioavail-
ability than PMs, indicating a significant contribution of
CYP2D6 to the first-pass metabolism of E-doxepin. These
findings indicate that the CYP2D6 genotype has a major im-
pact on E-doxepin pharmacokinetics that and PMs might be
at an increased risk of adverse drug effects when treated with
recommended standard doses. Koski et al.[35] have recently
reported a fatal case of a doxepin recipient who carried a
nonfunctionalCYP2D6*3/*4 allele. The plasma concentrations
of doxepin and nordoxepin were 2.4 and 2.9mg/L, respectively,with a ratio of doxepin/nordoxepin of 0.83, which was the
lowest found among the 35 nordoxepin-positive postmortem
cases in this study.[35] It is unknown whether there is a corre-
lation between the CYP2D6 phenotype/genotype and the
therapeutic effect of doxepin.
Imipramine and Desipramine
Imipramine was the first tricyclic antidepressant to be de-
veloped and is mainly used in the treatment ofmajor depression
and enuresis. Imipramine is rapidly and almost completely
metabolized, with the formation of desipramine via N-de-
methylation, 2-hydroxy metabolites and subsequent glucur-
onidation. Imipramine has high clearance (0.8–1.5 L/min) and
corresponding high first-pass elimination (30–70%).[36] Imi-
pramine, as a tertiary amine, is metabolized to desipramine
(a secondary amine) via CYP2C19, 3A4 and 1A2, and both
compounds are metabolized to their active 2-hydroxylated
metabolites largely by CYP2D6 (see supplementary figure 18,
Supplemental Digital Content 1).[37-39] Imipramine is also me-
tabolized by uridine diphosphate glucuronosyltransferase
(UGT) 1A4 to imipramineN-glucuronide, to aminor extent.[40]
Imipramine N-oxide and didesmethylimipramine are also
detected in human plasma and urine as minor metabolites.[41]
Brosen et al.[42] found that the oral clearance of imipramine
in PMs of substrates of CYP2D6 was approximately 53% of
that of EMs (1.35 vs 2.55 L/min) receiving a single oral dose of
100mg. 2-OH-imipramine was detectable in the plasma of EMs
but not in that of PMs, where the ratio to the parent compound
was higher in rapid EMs than in slow EMs. However, there was
no significant difference in the clearance of imipramine via
N-demethylation between PMs and slow and rapid EMs (1.06
vs 1.42 and 1.60L/min, respectively). These findings indicate
the primary role of CYP2D6 in 2-hydroxylation of imipramine
and desipramine, while their N-demethylation is mediated by
multiple CYP isoenzymes.
The AUC values of desipramine following a single dose
(100mg) in Caucasians have been shown to be 4- to 8-fold
higher in PMs than in EMs.[42-44] The mean steady-state con-
centrations were ~3-fold higher in PMs than in EMs.[45] The
oral clearance of desipramine was 0.19 L/min in PMs compared
with 1.64 and 1.03L/min in rapid EMs and slow EMs, respec-
tively.[42] A significantly longer elimination half-life (t½) of
desipramine was observed in PMs than in EMs (81–131 vs
13–23 hours). 2-OH-desipramine was detected in EMs only.
Similar effects have been seen in Japanese.[46] In one study, two
PMs received a greatly reduced dose compared with that given
to EMs (50 vs 200mg daily) and still attained plasma desipra-
mine concentrations at the upper end of the range observed in
EMs (860 and 880 vs 130–910 nmol/L).[29] The doses required
by EMs (200mg/day) would yield clearly toxic drug concen-
trations (>3.0 mmol/L) in PMs.
At steady state, the plasma concentration of imipramine
and desipramine have been shown to be significantly higher in
PMs than in EMs when treated with imipramine 100mg/day(imipramine: 302–455 vs 169nmol/L; desipramine: 1148–1721 vs
212nmol/L).[47] The ratios of 2-OH-imipramine to imipramine
and of 2-OH-desipramine to desipramine were 5- to 10-fold
higher in EMs than in PMs. Desipramine concentrations at
steady state are 7-fold higher in PMs, with the sum of imipramine
plus desipramine concentrations being 5-fold higher in PMs
than in EMs.[47] The urinaryMRvalues of sparteine and debriso-
quine correlated poorly with imipramine steady-state concentra-
tions but quite well with desipramine steady-state concentrations.
There were significant negative correlations between the MRs of
sparteine and debrisoquine and the 2-OH-imipramine/imipramine
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and 2-OH-desipramine/desipramine ratios. In addition, there
was a weak negative correlation between the sparteine MR and
the daily dose of imipramine required to achieve therapeutic
range.[47] These results further support the primary role of
CYP2D6 in 2-hydroxylation of imipramine and desipramine. The
sum of imipramine plus desipramine concentrations may be used
to conduct therapeutic monitoring during treatment with imipra-
mine, and PMs generally require lower doses to achieve the target
concentrations. PMs have been shown to need 20–25mg/day of
imipramine, whereas EMs required 50–350mg/day to attain
summed concentrations of ~300–500 nmol/L in patients with
diabetic neuropathy.[48] It is unknown whether the CYP2D6
phenotype status affects the adverse effects of imipramine.
In one steady-state study in patients with depression, com-
prising two PMs and 29 EMs receiving desipramine 100mg/dayfor 3 weeks, three patients (including both PMs and one EM)
required a dosage decrease because of marked adverse effects
(e.g. sedation or postural hypotension).[45] Plasma desipramine
concentrations were significantly correlated with dextro-
methorphan MRs, with the two PMs showing the highest
plasma concentrations of desipramine. At 3weeks, there was no
significant correlation between plasma concentrations of either
desipramine or desipramine plus 2-OH-desipramine and the
antidepressant effect when assessed by the Hamilton Depres-
sion Rating Scale.[45] These results indicate that the CYP2D6
phenotype status has a significant impact on steady-state
plasma concentrations of desipramine in patients with depres-
sion and may identify patients at increased risk of severe con-
centration-dependent CNS adverse effects. However, CYP2D6
activity does not appear to predict the therapeutic effect of
desipramine, which is not concentration dependent.
A recent retrospective study by Schenk et al.[49] in 181 patients
with depression revealed that the plasma concentrations of desi-
pramine and the sum of imipramine plus desipramine per drug
dose unit, the imipramine dose at steady state and the imipramine
dose requirement significantly depended on the CYP2D6 geno-
type. The mean dosage requirements of imipramine were 131,
155, 217, 245, 326 and 509mg daily in carriers of 0, 0.5, 1, 1.5, 2
and >2 active CYP2D6 genes, respectively. These results suggest
that genotype-based drug dose recommendationsmight allow for
the use of an adjusted starting dose and faster achievement of pre-
defined imipramine plus desipramine plasma concentrations in
the management of imipramine pharmacotherapy, which would
improve therapeutic efficacy andminimize adverse drug reactions.
Maprotiline
Maprotiline is a tetracyclic antidepressant, which is a selective
norepinephrine reuptake inhibitor with very weak inhibitory ef-
fect on dopamine and serotonin reuptake.[50] Maprotiline is
mainlymetabolized byCYP2D6 (~83%), and to a lesser extent by
CYP1A2 (~17%), to its major active metabolite, N-desmethyl-
maprotiline (normaprotiline), via N-demethylation (see supple-
mentary figure 19, Supplemental Digital Content 1).[51] Mapro-
tiline is also metabolized by deamination, aliphatic and aromatic
hydroxylation and by formation of aromatic methoxy deriva-
tives. Formation of 3-OH-maprotiline, 2-OH-maprotiline and
2,3-dihydrodiol with subsequent glucuronidation plays a less
important role in the overall elimination of maprotiline.[52] Sev-
eral clinical studies have indicated the important role of CYP2D6
in the metabolism of maprotiline. A study in patients with
depression found that fluvoxamine inhibited the N-demethyla-
tion of maprotiline,[53] and another study found that risperidone
increased plasma concentrations of maprotiline.[54] In studies of
therapy-resistant patients with depression treated with maproti-
line, coadministration of moclobemide significantly increased
maprotiline plasma concentrations by 25%.[55] Moclobemide is a
known inhibitor of CYP2D6, 1A2 and 2C19.[56]
In healthy subjects, the peak plasma concentration (Cmax)
and AUC of maprotiline were 2.7- and 3.5-fold higher, re-
spectively, in PMs (n = 6) than in EMs (n = 6) receiving 50mg
twice daily for 8 days (Cmax 203 vs 73 ng/mL; AUC from 0 to
48 hours [AUC48h] 8054 vs 2289 ng � h/mL).[57] PMs had a
2.9-fold longer t½ than EMs (88.3 vs 30.4 hours). The duration
of the pulmonary effect of maprotiline (alleviation of hista-
mine-induced bronchoconstriction) after cessation of 8-day
maprotiline treatment in EMs was <3 weeks compared with
‡4 weeks in PMs.[57] Lower plasma concentrations of mapro-
tiline were associated with a marked decrease in bronchial
sensitivity to histamine. These results demonstrate a clear gene-
dose effect on maprotiline. However, no data are available on
the effect of the CYP2D6 phenotype on the efficacy and adverse
effects of maprotiline in patients with depression.
Trimipramine
Trimipramine, a tricyclic antidepressant used as a racemate,
is a moderate inhibitor of norepinephrine reuptake and a weak
inhibitor of serotonin and dopamine reuptake.[58] Trimipra-
mine is converted to 2-hydroxytrimipramine and 2,10- or 2,11-
dihydroxytrimipramine by CYP2D6 (see supplementary figure
20, Supplemental Digital Content 1).[59] N-glucuronide and
glucuronides of the hydroxylated metabolites are also detected
in human urine. There is marked enantioselectivity in the me-
tabolism of trimipramine, with a preferential N-demethylation
for (D)-trimipramine and a preferential hydroxylation for
(L)-trimipramine.[60] CYP2D6 catalyses the 2-hydroxylation of
(L)-trimipramine and (L)- and (D)-desmethyltrimipramine
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(nortrimipramine), while CYP2C19 catalyses the demethyla-
tion of (D)- and (L)-trimipramine.[60] The activity of N-des-
methyltrimipramine is considered to be similar to that of its
parent molecule.
Because of the differing role of CYP2D6 and 2C19 in the
metabolism of trimipramine enantiomers, the phenotype of both
CYP2D6 and 2C19 would affect the disposition of racemic tri-
mipramine. In patients with depression (n= 27), the sole PM of
substrates of CYP2D6 receiving racemic trimipramine 300 and
400mg/day had the highest concentrations of (L)- and (D)-des-
methyltrimipramine, which were formed by CYP2C19, while the
sole PM of substrates of CYP2C19 showed the highest con-
centration of (L)- and (D)-trimipramine.[60] A single-dose (75mg)
study in 42 healthy subjects indicated that the disposition of tri-
mipramine and its demethylated metabolite was associated with
the CYP2D6 phenotype.[61] Oral clearance of trimipramine was
36L/h in healthy PMs but 276L/h in EMs. The bioavailability of
trimipramine was 3-fold higher in PMs of substrates of CYP2D6
than in EMs. The AUC of desmethyltrimipramine was 40-fold
higher in PMs of substrates of CYP2D6 than in EMs (1.7 vs
0.04mg � h/L), but this metabolite was undetectable in most PMs
of substrates of CYP2C19 or 2C9.[61] However, the plasma con-
centration of 2-hydroxytrimipramine was very low in PMs of
substrates of CYP2D6. These findings demonstrate a major
role of CYP2C9 and 2C19 in the N-demethylation of trimipra-
mine, and CYP2D6 is involved in its further metabolism
(e.g. 2-hydroxylation). The genotype/phenotype of CYP2D6,
2C19 and possibly 2C9 can affect the disposition of trimipramine.
CYP2D6 appears to favour trimipramine hydroxylation but not
its N-demethylation. This has been confirmed by an interaction
study with the CYP2D6 inhibitor quinidine, which increased the
plasma concentration of trimipramine, whereas the formation
of 2-hydroxytrimipramine was decreased.[62] Cases have been
reported in which trimipramine concentrations were increased by
coadministered paroxetine.[63] A fatal case has been documented
in which trimipramine and citalopram were combined.[64]
Summary of Tricyclic Antidepressants
Tricyclic antidepressants have similar metabolic routes and
complex pharmacology. CYP2D6 has differing contributions
to their metabolic clearance, and pharmacologically active meta-
bolites canbe formed fromCYP2D6-mediated pathways. There is
possible enantioselective disposition. Thus, it is difficult to esta-
blish clear relationships of their pharmacokinetic and pharmaco-
dynamicparameterswith genetic variations ofCYP2D6.Although
initial gene-dose effects have been observed for some tricyclic
antidepressants, dosage adjustment based on the CYP2D6
phenotype cannot be recommended at present.
1.1.2 Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs), including
citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline,
possess a similar mechanism of action (i.e. inhibition of neu-
ronal reuptake of serotonin mediated by the monoamine
transporter SLC6A4), but they are chemically unrelated and
show remarkable differences in their metabolism and phar-
macokinetic profiles.[2,65,66] Fluoxetine, fluvoxamine and par-
oxetine, but not sertraline and citalopram, exhibit nonlinear
pharmacokinetics.[66]Most SSRIs have a t½ of approximately 1
day. However, fluoxetine has a t½ of 2–4 days, and its active
metabolite, norfluoxetine, has an extended t½ of 7–15 days.[67]
All of these SSRIs are metabolized by CYP2D6 to a certain
extent, with variable contributions from CYP2C19, 2C9 and
3A4. With the exception of N-demethylated fluoxetine, meta-
bolites of SSRIs usually do not contribute to their clinical
efficacy. Paroxetine, fluoxetine and norfluoxetine, but
not citalopram and fluvoxamine, are potent inhibitors of
CYP2D6.[66] Paroxetine is a mechanism-based inhibitor of
CYP2D6.[68] Fluoxetine, paroxetine and fluvoxamine, but not
citalopram and sertraline, inhibit their own metabolism.[67]
SSRIs are considered to have higher therapeutic indices than
those of tricyclic antidepressants. However, SSRIs can produce
a wide range of adverse effects at clinical concentrations, which
are associated with the potentially fatal serotonin syndrome.
Like most tricyclic antidepressants, SSRIs are lipid-soluble
drugs with a high clearance.
Citalopram
Citalopram, an SSRI used to treat major depression asso-
ciated with mood disorders, is converted to N-desmethylcitalo-
pram (norcitalopram) and then to N,N-didesmethylcitalopram
and citalopramN-oxide.[69] CYP3A4 (35%), 2C19 (35%) and 2D6
(30%) are involved in the first demethylation step of citalopram,
all favouring conversion of the biologically active S-enantiomer
(escitalopram) [see supplementary figure 21, Supplemental Di-
gital Content 1).[70,71] One study found that CYP2D6 exclusively
catalysed the second demethylation step, and citalopramN-oxide
was also formed by CYP2D6 only.[70]
Following oral administration of racemic citalopram to
healthy subjects, the AUC of S-citalopramwas shown to be sig-
nificantly higher in those who were EMs of CYP2D6 substrates
but PMs of CYP2C19 substrates compared with those who
were EMs of CYP2D6 and CYP2C19 substrates and those who
were PMs of CYP2D6 substrates but EMs of CYP2C19 sub-
strates. In contrast, the AUC of R-citalopram did not differ
between the different genotype/phenotype groups.[72] Similar
differences (although they did not reach statistical significance)
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were observed for S- and R-desmethylcitalopram. However, a
recent study of 1953 patients with depression did not reveal an
association between theCYP2D6 genotype and the response to
and tolerance of citalopram.[73] The CYP2D6 genotype and
phenotype status did not correlate with the dosage of citalo-
pram and the duration of citalopram therapy. A large Swedish
study (n = 749) found no difference in citalopram or des-
methylcitalopram plasma concentrations between those who
experienced a number of common adverse effects and those
who did not, suggesting that adverse effects of citalopram are
determined primarily by pharmacodynamic rather than phar-
macokinetic factors.[74] It appears that knowledge of the
CYP2D6 genotype/phenotype would not assist with proper
dosage adjustment of citalopram.
Fluvoxamine
Fluvoxamine, one of the first SSRIs developed, is used in the
treatment of major depression and anxiety disorders.[75,76]
Fluvoxamine is extensively metabolized in the human liver
via oxidative demethylation and oxidative deamination and
N-acetylation, and <4% is excreted in its unchanged form.[77]
Approximately 30–60% of the metabolites appear to be pro-
duced by oxidative demethylation of the methoxy group,
whereas 20–40% seems to be produced by oxidative deamina-
tion to fluvoxethanol or by removal of the entire ethanolamino
group.[78] Fluvoxamine appears to be converted to its major
urinary metabolite – the 5-demethoxylated carboxylic acid
metabolite, which is pharmacologically inactive – mainly by
CYP2D6 and, to a lesser extent, by CYP1A2 (see supplemen-
tary figure 22, Supplemental Digital Content 1).[79] No other
active metabolites are formed from fluvoxamine.[80] Relative to
other SSRIs, fluvoxamine is a potent inhibitor of CYP1A2, a
moderate inhibitor of CYP2C19 and 3A4, and a weak inhibitor
of CYP2D6,[81] and a number of drug interactions with flu-
voxamine have been documented.[82,83]
One study found that clearance of the 5-demethoxylated
carboxylic acid metabolite was 78% lower in PMs of substrates
of CYP2D6 than in EMs after a single oral dose of fluvox-
amine, but smoking and being a PM of substrates of CYP2C19
did not influence its clearance.[79] There was no significant
correlation between oral caffeine clearance (CYP1A2-mediated)
and clearance of this metabolite.[79] A single-dose study ob-
served a 1.3-fold higher AUC of fluvoxamine in PMs,[79]
whereas another study found no difference between PMs and
EMs.[84] Similar disparities were observed at steady state.[77,84]
It appears that the CYP2D6 genotype has an effect on the
adverse effects of fluvoxamine. In a study in Japanese patients
with depression (n = 100), carriers of the CYP2D6*5 and *10
alleles showed increased gastrointestinal adverse effects in-
duced by fluvoxamine compared with the wild-type, and there
was a 4.2-fold higher risk of developing gastrointestinal adverse
effects, compared with EMs, when the nonfunctional CYP2D6
allele was combined with the 5-HT2A receptor A-1438G poly-
morphism.[85] However, the plasma concentrations of fluvox-
amine were not determined in this study.
These results suggest that CYP2D6 genotype has only a
marginal effect on the clearance of fluvoxamine, since the
contribution of CYP2D6 to the overall clearance of fluvox-
amine is minor to moderate, and other enzymes such as
CYP1A2may play amore important role in its clearance. There
is weak evidence of an association between the CYP2D6 phe-
notype and the efficacy of and adverse reactions to fluvox-
amine. Kirchheiner et al.[86] have suggested that homozygous
EMswould need 120% of the recommended dose, heterozygous
EMs would need 90% of the recommended dose, and PMs
would need 60% of the recommended dose in order to achieve
the same plasma concentrations of fluvoxamine. However, as
fluvoxamine has a broad therapeutic index, and the inter-
individual metabolic variability within EMs and PMs is high,
the need to adjust its dose on the basis of the CYP2D6 phe-
notype seems to be relatively small.
Fluoxetine
Fluoxetine is a potent SSRI, commonly prescribed as an
antidepressant agent. Fluoxetine is indicated for the treat-
ment of major depression (including depression in children),
obsessive-compulsive disorder in both adult and paediatric
patients, bulimia nervosa, anorexia nervosa, panic disorder and
premenstrual dysphoric disorder. Fluoxetine is metabolized
extensively by hepatic CYP enzymes.[87] There are two major
metabolic routes for fluoxetine: N-demethylation to nor-
fluoxetine (N-desmethylfluoxetine) and O-dealkylation to
p-trifluoromethylphenol.[81] CYP2D6 is largely responsible for
the formation of active R- and S-norfluoxetine from fluoxetine
via N-demethylation at low concentrations, with increased
contributions from CYP3A4 and 2C9 when substrate concen-
trations increase and CYP2D6 becomes saturated (see supple-
mentary figure 23, Supplemental Digital Content 1).[88,89]
R- and S-fluoxetine and S-norfluoxetine are equally potent
SSRIs, but R-norfluoxetine is 20-fold less potent in this regard.
Norfluoxetine undergoes further oxidative deamination to
form the alcohol and acid derivatives.
The AUC of fluoxetine was 3.9-fold higher and that of
norfluoxetine was 0.5-fold lower in PMs than in EMs receiving
a single oral dose of 20mg, whereas the sum of these moieties
was 1.3-fold higher in PMs.[90] When the dose was increased to
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60mg, the median AUC values of S- and R-fluoxetine were
11.5- and 2.4-fold higher, respectively, in PMs, whereas S- andR-
norfluoxetine were decreased by only ~20–40%.[91] In PMs, the
oral clearance values of R- and S-fluoxetine were 3.0 and 17L/h,respectively, while the corresponding values in EMs were 36 and
40L/h. In PMs, the t½ values were 6.9 and 17.4 days for R- and
S-norfluoxetine, respectively, and 5.5 days for both enantiomers
in EMs, with a significant phenotypic difference only for
S-norfluoxetine. The t½ values of R- and S-fluoxetine were 9.5
and 6.1 days, respectively, in PMs but decreased to 2.6 and 1.1
days, respectively, in EMs. These results indicate that CYP2D6
extensively metabolizes R- and S-fluoxetine and most likely
the further metabolism of S-norfluoxetine but not of R-
norfluoxetine. The CYP2D6 phenotype has a marked impact on
the pharmacokinetics of fluoxetine.
The sum of the racemic parent drug plus norfluoxetine
trough concentrations was comparable between PMs and EMs
receiving fluoxetine 20mg/day for 23 days in a steady-state
study.[91] There was no significant difference in the plasma
concentrations of R-fluoxetine and R-norfluoxetine, whereas
the concentration of S-fluoxetine was 2.2-fold higher and that
of S-norfluoxetine was 3.4-fold lower in PMs than in EMs.[91]
In another steady-state study in 78 patients with depression,
there was no significant relationship between the CYP2D6
genotypes and the dose-normalized plasma concentrations of
both enantiomers of fluoxetine or their active moieties (i.e. the
sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine).[92]
However, the plasma concentration of S-norfluoxetine was very
low in the only PM subject and the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in het-
erozygous EMs. These findings have provided further evidence
that CYP2D6 mediates the demethylation of fluoxetine to
norfluoxetine, with stereoselectivity towards the S-enantiomer;
CYP2D6 polymorphisms contribute to the wide interindividual
variability in fluoxetine pharmacokinetics at steady state.
It appears that the CYP2D6 phenotype status does not affect
the incidence of adverse reactions to fluoxetine. In studies with
small samples, a significant relationship between the CYP2D6
status and adverse reactions of fluoxetine has not been ob-
served.[21,93] In the clinical study with 20 patients with depres-
sion by Stedman et al.,[93] fluoxetine- or paroxetine-induced
hyponatraemia was not associated with nonfunctional
CYP2D6 alleles such as *4, *5 and *6. Conversely, the trend
was in the opposite direction, suggesting that hyponatraemia
induced by SSRIs is explained by factors other than genetically
poor metabolism of CYP2D6, such as alterations in the renin-
angiotensin system related to increased age, and other
co-morbidities and co-medication.
Paroxetine
Paroxetine is an SSRI commonly used in the management of
major depression, obsessive-compulsive disorder and panic
disorder.[94] Approximately 64% of a 30mg oral dose of par-
oxetine is excreted in the urine, with 62% as metabolites, over a
10-day postdosing period. The principal metabolites of par-
oxetine are polar conjugates of oxidative and methylated me-
tabolites. Paroxetine is mainly (80%) metabolized by CYP2D6
via demethylenation of themethylenedioxy group, giving rise to
an inactive catechol metabolite, which is then either O-methy-
lated orO-glucuronidated, and the by-product formic acid (see
supplementary figure 24, Supplemental Digital Content 1).[95]
Saturation and mechanism-based inhibition of CYP2D6 by
paroxetine at clinical doses appears to explain the nonlinear
pharmacokinetics of paroxetine with increasing dose and in-
creasing duration of treatment.
Several clinical studies have shown a relationship bet-
ween the CYP2D6 phenotype/genotype and paroxetine con-
centrations during short- or long-term dosing.[96-98] Sindrup
et al.[96] found that the median AUC of paroxetine was 7-fold
higher in PMs than in EMs treated with a single dose at 30mg
(550 vs 3910 nmol � h/L), but the AUC difference decreased to
2-fold at steady state with 30mg/day for 2 weeks (2550 vs
4410 nmol � h/L). The plasma t½ and steady-state plasma
concentration were significantly longer and higher in PMs than
in EMs (41 vs 16 hours and 151 vs 81 nmol/L, respectively).Paroxetine displayed nonlinear pharmacokinetics in EMs but
not in PMs.[96] These results indicate that the inter-phenotype
difference in paroxetine metabolism was less prominent at
steady state than after a single dose, presumably due to satur-
able CYP2D6-mediated metabolism. Sparteine MRs increased
in EMs during paroxetine treatment, and two EMs were phe-
notyped as PMs and the remaining EMs were converted into
extremely slow EMs, with MRs of 5.7–16.5 after 14 days’
treatment.
Sindrup et al.[97] conducted another steady-state study with
more paroxetine dose levels (10–70mg/day) in 13 EMs and
three or four dose levels (10–40mg/day) in three PMs, all
treated for diabetic neuropathy symptoms. They reported
3.3-fold higher 12-hour concentrations of paroxetine in PMs
than in EMs and a 25-fold variation in steady-state con-
centrations of paroxetine (25–670 nmol/L).[97] The steady-stateconcentrations of paroxetine at all dose levels showed a positive
correlation with sparteine MRs in EMs. Estimates of clearance
at low drug concentrations of the high-affinity clearing process
showed a significant negative correlation with the sparteine
MRs, but the clearance of the low-affinity process was not re-
lated to the MRs in both EMs and PMs.[97] These data indicate
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that the metabolism of paroxetine and sparteine cosegregates
and that CYP2D6 is responsible for a high-affinity saturable
paroxetine elimination process.
Heterozygous EMs had nonsignificantly 2-fold higher
median steady-state trough concentrations of paroxetine than
homozygous EMs did, with a considerable overlap in the
distribution of paroxetine concentrations between the two
phenotypes.[98] No PMs or UMs were included in this study.
Notably, UMs had very low or undetectable concentrations
of paroxetine with common doses.[99,100] These subjects would
be expected to be undertreated if the paroxetine dosage is not
increased.
Evidence of the effect of the CYP2D6 phenotype on the
therapeutic efficacy and adverse reactions of SSRIs is weak.
One study in 30 patients found that sexual dysfunction was
more frequent in EMs who were converted into PMs during
treatment (17/24 patients; 71%) than in those who were phe-
notyped as EMs (2/6 patients; 33%).[101] In a prospective study
of 246 elderly patients taking paroxetine together with another
medication that is a CYP2D6 substrate, the CYP2D6 genotype
was not associated with the incidence of adverse effects.[102] The
CYP2D6 genotype did not correlate with the incidence of
paroxetine-induced nausea.[103] The safety margin of SSRIs
may be sufficient to prevent the occurrence of more adverse
effects in IMs and PMs. However, since most SSRIs are potent
CYP2D6 inhibitors, they can thus convert an EM to PM status,
probably resulting in remarkable toxicity. Furthermore, one
study demonstrated no correlation between concentrations of
paroxetine and its therapeutic effect.[99]
Summary of Selective Serotonin Reuptake Inhibitors
There is preliminary evidence of a gene-dose effect on com-
monly used SSRIs, and data on the effect of the CYP2D6 geno-
type/phenotype on the response to and adverse effects of SSRIs
are scanty. Therefore, recommendations for dose adjustment of
prescribed SSRIs based on the CYP2D6 phenotype/genotypemay be premature, and further studies are warranted to explore
the impact of the CYP2D6 genotype/phenotype on the phar-
macology of SSRIs.
1.1.3 Other Antidepressants
Mianserin
Mianserin is a tetracyclic piperazinoazepine antidepressant
administered as a racemic mixture, and its antidepressant ac-
tivity and disposition exhibit stereoselectivity.[104] The major
metabolic routes of mianserin include para-oxidation of the
N-substituted aromatic ring (i.e. 8-hydroxylation) followed by
phase II conjugation, and oxidation (to form N-oxide) and
demethylation of the N-methyl moiety, followed by phase II
conjugation.[105] Mianserin also undergoes direct conjugation
of theN-methyl moiety to formN+-glucuronide in humans.[105]
CYP2D6 is involved in the 8-hydroxylation, N-demethyla-
tion and N-oxidation of mianserin, with CYP3A4 and 1A2
being major contributors to the generation of desmethylmian-
serin (see supplementary figure 25, Supplemental Digital Con-
tent 1).[106,107] S-mianserin is more reliant on CYP2D6[108,109]
and may have a greater antidepressant effect thanR-mianserin.
N-desmethylmianserin is pharmacologically active.
In one study, the mean AUC values of mianserin and des-
methylmianserin were 1.8- and 1.5-fold higher, respectively, in
PMs than in EMs.[108] A PM of both debrisoquine and me-
phenytoin had the highest summed concentrations among 18
patients with diabetic neuropathy,[110] and three of six patients
with high mianserin concentrations were phenotypic PMs in
another study.[111] In contrast, only one of seven patients with
slow mianserin elimination was a PM, which does not support
an important role for CYP2D6 in the elimination of mianser-
in.[112] Higher mean S-mianserin plasma concentrations (15 vs
8mg/L at 12 hours postdose) and a slightly greater response
were observed in Japanese patients with depression harbouring
CYP2D6*1/*10 compared with those harbouring *1/*1 who
received mianserin 30mg daily for 3 weeks.[113] Thioridazine
inhibited CYP2D6 and increased S-mianserin, S-desmethyl-
mianserin and R-desmethylmianserin concentrations by 1.9-,
2.1- and 2.7-fold, respectively, whereas there was no effect on
R-mianserin pharmacokinetics.[109]
Mirtazapine
Mirtazapine is the first noradrenergic and specific serotonergic
antidepressant acting at presynaptic a2-receptors and post-
synaptic 5-HT2 receptors and is used as a racemate.[114] Mirta-
zapine has linear pharmacokinetics over a dose range of
15–80mg.[115] Mirtazapine is extensively metabolized in humans,
and its primary oxidative metabolites are 8-hydroxymirtazapine,
N-desmethylmirtazapine (normirtazapine) and mirtazapine-
N-oxide.[116] The pharmacokinetics of mirtazapine are en-
antioselective, with higher plasma concentrations and a longer
half-life of the R-enantiomer compared with that of the S-
enantiomer. Mirtazapine is mainly metabolized by CYP2D6
(~35%), with substantial contributions from CYP1A2 and 3A4
(see supplementary figure 26, SupplementalDigital Content 1).[106]
Genetic CYP2D6 polymorphisms have shown different ef-
fects on the disposition of the enantiomers of mirtazapine. The
AUC of S-mirtazapine was 79% larger in PMs than in EMs, but
there were no differences between EMs and PMs in the phar-
macokinetics of theR-enantiomer.[115] A population-modelling
770 Zhou
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study in 49 patients with depression reported 26% lower
clearance of mirtazapine in IMs than in EMs.[117]
A single-dose study in 25 healthy subjects demonstrated that
the median oral clearance values of racemic mirtazapine were
20.1, 39.7 and 49.8 L/h in carriers of 0, 2 (*1/*1) and three activegenes of CYP2D6, respectively, and the median Cmax values
were 129, 159 and 76 mg/L, respectively, in these three groups,
indicating a contribution of CYP2D6 to the first-pass meta-
bolism of mirtazapine.[118] There was a trend for lower concen-
trations of the active metabolite desmethylmirtazapine in the
group with three functional alleles (i.e. UMs), but it did not
achieve statistical significance. Mirtazapine concentrations were
significantly correlated with blood pressure, and the correlation
was even stronger when considering the sum of mirtazapine plus
desmethylmirtazapine, but the effect on blood pressure and
heart rate was not correlated with the CYP2D6 genotype.[118]
These results indicate that CYP2D6 contributes to ~25% of
total clearance of mirtazapine in individuals carrying only one
active allele of CYP2D6 and up to 55% in UMs. The effect of
the CYP2D6 gene duplication was lower than expected, and
high CYP2D6 activity may explain only a small percentage of
the cases with therapeutic failure in mirtazapine treatment.
A recent study by Brockmoller et al.[119] revealed that the
pharmacokinetics of R-mirtazapine were only marginally in-
fluenced by the CYP2D6 genotype, but the oral clearance va-
lues of the S-enantiomer were 1.3, 2.3 and 3.4mL/min in PMs,
EMs and UMs, respectively, indicating substantial first-pass
metabolism of mirtazapine in EMs and UMs. Mirtazapine was
enantioselectively absorbed from the small intestine, with rate
constants of 0.2min-1 for S-mirtazapine but 0.08min-1 for
R-mirtazapine.[119] The effect of mirtazapine on the heart rate,
blood pressure and sedation was correlated with both R- and
S-mirtazapine plasma concentrations. These results demon-
strate a gene-dose effect on S-mirtazapine but not the
R-enantiomer, since the disposition of the S-enantiomer is more
dependent on CYP2D6. However, the adverse effects of mirta-
zapine appear to correlate with both S- and R-mirtazapine
concentrations.
Venlafaxine
Venlafaxine is a mixed serotonin and norepinephrine re-
uptake inhibitor used as a first-line treatment for depressive
disorders.[120] After oral administration, venlafaxine undergoes
extensive first-pass metabolism by the liver to two minor and
less active metabolites, N-desmethylvenlafaxine and N,O-di-
desmethylvenlafaxine, and a major metabolite, O-desmethyl-
venlafaxine (norvenlafaxine), which is an activemetabolite with
antidepressant activity comparable to that of the parent drug
(see supplementary figure 27, Supplemental Digital Content
1).[121] Venlafaxine is converted by CYP2D6 to its active me-
tabolite O-desmethylvenlafaxine, while its N-demethylation is
catalysed by CYP3A4, 2C19 and 2C9.[68,122] All demethylated
metabolites of venlafaxine can be further conjugated by
glucuronidation.
A good correlation has been demonstrated between the deb-
risoquine MR and the ratio between the AUC of venlafaxine
and that of O-desmethylvenlafaxine.[123] PMs had more than
4-fold lower oral clearance of venlafaxine than EMs, mainly due
to decreased capacity to form the O-demethylated metabo-
lites.[124] In a study involving 33 patientswith depression receiving
venlafaxine 225mg daily, a significant relationship between the
CYP2D6 genotype and the O-desmethylvenlafaxine/venlafaxineratio was found, with PMs having extremely low ratios and
UMs having high ratios compared with homozygous and het-
erozygous EMs.[125] Healthy Japanese subjects with homozygous
CYP2D6*10 allele had a 4.5-fold higher plasma AUC of venla-
faxine than the wild-type (EMs).[126] At steady state, the median
oral clearance of R-venlafaxine was 9-fold higher in EMs than in
PMs, while it was 2-fold higher for S-venlafaxine.[127] Coadmi-
nistration of quinidine to EMs resulted in almost complete
inhibition of the partial metabolic clearance of R-venlafaxine
to O-demethylated metabolites, while a 7-fold decrease was
observed for S-venlafaxine.[127] These findings indicate that
although CYP2D6 catalyses the O-demethylation of both
enantiomers of venlafaxine, it shows marked stereoselectivity
towards the R-enantiomer.
In a single-dose study in healthy subjects, the dose-corrected
AUC of venlafaxine was 2.3-fold higher and that of its active
metabolite O-desmethylvenlafaxine was 3.4-fold lower in PMs
than in EMs.[123] In a recent study of 46 elderly patients with
major depression receiving venlafaxine-XR (extended release),
it was found that the plasma concentration of venlafaxine was
significantly higher and the O-desmethylvenlafaxine con-
centration per unit dose was significantly lower in patients
carrying one or more variant alleles, compared with the wild-
type.[128] This study did not find an association between the
CYP2D6 genotype and adverse effects. Another study reported
that patients with O-desmethylvenlafaxine/venlafaxine ratios
below 0.3 were all identified as PMs, while individuals with
ratios above 5.2 were all UMs because of gene duplications.[129]
Five patients with intermediate metabolic activity were het-
erozygous forCYP2D6*4. In this study, PMs experiencedmore
adverse effects (mainly nausea and vomiting).[129]
A recent steady-state study reported that the plasma con-
centration of N-desmethylvenlafaxine was 5.5-fold higher in
heterozygous EMs and 22-fold higher in PMs than in EMs.[130]
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This study suggests that there is a shift in the metabolic
pathway, resulting in substantially higher concentrations
of N-desmethylvenlafaxine in heterozygous EMs and PMs.
Decreased CYP2D6 activity due to genetic mutation or in-
hibition by quinidine could be associated with cardiovascular
toxicity, as was observed in four patients during treatment with
venlafaxine.[124] The reported adverse effects included palpita-
tions, shortness of breath and proarrhythmias due to the het-
erogeneity in cardiac repolarization. Genetic variations in the
CYP2D6 gene may contribute to interpatient variation in
response to venlafaxine treatment. An adverse reaction may
indicate a slow metabolizer, and a genotyping test should be
considered for such patients.[131]
Miscellaneous Antidepressants
The CYP2D6 status has little impact on the clearance and
effect of sertraline (an SSRI), which is metabolized by CYP2C19,
2C9 and 2D6.[132] There have been documented cases of toxicity
in PMs treated with nortriptyline[133] or desipramine.[134] On the
other hand, lack of response was seen in UMs treated with nor-
triptyline and other tricyclic antidepressants.[23,135]
In a retrospective study of 28 patients who experienced ad-
verse events and 16 patients who were nonresponsive to a
variety of antidepressants, Rau et al.[136] observed an associa-
tion with the CYP2D6 genotype. The authors found that 29%of individuals with adverse reactions to antidepressants (most
commonly tricyclic antidepressants) were PMs, whereas 19%(3/16) of nonresponders were UMs (4- and 5-fold higher than
expected, respectively). A higher rate of CYP2D6 gene dupli-
cation was observed in 108 patients who had depression treated
with antidepressants metabolized by CYP2D6, in whom the
therapy failed (9.9% vs 0.8–1% expected).[137] In a study of
136 Caucasian inpatients with depression treated with ami-
triptyline, citalopram, clomipramine, doxepin, fluvoxamine,
mirtazapine, paroxetine, sertraline and venlafaxine, a non-
functional CYP2D6 genotype and co-medication with in-
hibitors of CYP2D6 were associated with higher plasma
concentrations of antidepressants when normalized to dose;
five of the six PMs experienced adverse effects.[138]
A recent large population-based cohort study in 1198 elderly
Dutch patients examined the influence of the CYP2D6*4polymorphism on intolerability of antidepressants.[139] The risk
of switching to another antidepressant was higher in PMs using
tricyclic antidepressants, with an adjusted odds ratio of 5.77,
but not in those using SSRIs. Heterozygous patients did not
have an increased risk of switching in both tricyclic anti-
depressant and SSRI users. PMs require a lower maintenance
dose of tricyclic antidepressants or SSRIs than EMs do.[139]
The CYP2D6 status appears to affect hyponatremia asso-
ciated with the use of tricyclic antidepressants and SSRIs
in depressed patients. A population-based cohort study in
76 patients has demonstrated that patients carrying a homo-
zygous CYP2D6*4/*4 allele (n = 5) had a significantly lower
plasma sodium level than patients with the wild-type genotype
(*1/*1, n = 53).[140] PMs might be at a higher risk of developing
hyponatremia.
1.1.4 Summary of Antidepressants
The CYP2D6 genotype can be used to predict the plasma
concentrations of some tricyclic antidepressants, based on a
clear gene-concentration effect and SSRIs, and prospective
genotyping for CYP2D6 may identify individuals at increased
risk of adverse effects or therapeutic failure with anti-
depressants. However, although it is clear that toxicity and
treatment failures are major issues in psychiatry, most adverse
effects and therapeutic failures are seen in EMs rather than in
PMs or UMs, indicating the importance of pharmacodynamic
factors and other factors affecting the response to anti-
depressants. Furthermore, although recommendations for do-
sage adjustment of antidepressants based on the CYP2D6
genotype have been proposed,[141] the effectiveness of this ap-
proach has not been validated. Accurate prediction of the re-
sponse on the basis of variants of candidate genes such as
CYP2D6 remains elusive.
1.2 Antipsychotics
First-generation antipsychotics are known as ‘typical anti-
psychotics’ and include chlorpromazine, chlorprothixene, halo-
peridol, flupenthixol, fluphenazine, mesoridazine, perphenazine,
promazine, promethazine, thiodazine, triflupromazine and zu-
clopenthixol.[142] Most of the drugs in the second generation,
known as ‘atypical antipsychotics’, have been developed more
recently. Second-generation antipsychotics include amisulpride,
aripiprazole, clozapine, olanzapine, paliperidone, quetiapine,
risperidone, sertindole, ziprasidone and zotepine.[142-144] Both
classes of medication tend to block dopamine D2 receptors in the
dopamine pathways of the CNS, but antipsychotic drugs en-
compass a wide range of receptor targets.[142] For example, ris-
peridone also inhibits 5-HT2A receptors.[145] Second-generation
antipsychotics not only have the advantage of better extra-
pyramidal tolerability than classical antipsychotics but also
have a broader efficacy spectrum. Most antipsychotics have a
moderate to high therapeutic index but are associated with a
range of adverse effects – in particular, extrapyramidal reactions
772 Zhou
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such as acute dystonias, akathisia, hypotension, impotence, le-
thargy, seizures, nightmares, hyperprolactinaemia, tachycardia,
tardive dyskinesia, tardive psychosis and tremor. Newer anti-
psychotic agents, such as asenapine, bifeprunox, norclozapine
and iloperidone, are being developed.[146] Antipsychotics are
generally highly lipid soluble, subject to high clearance and
eliminated by metabolic rather than renal pathways. CYP2D6 is
involved in the metabolism of a variety of antipsychotics, in-
cluding thioridazine, quetiapine, perphenazine, chlorpromazine,
fluphenazine, haloperidol, zuclopenthixol, risperidone, aripi-
prazole and sertindole.[147-149] CYP3A4 and 1A2 are also in-
volved or play a major role in the metabolism of antipsychotic
drugs such as clozapine, olanzapine, quetiapine, pimozide and
haloperidol. There is initial evidence that theCYP2D6 statusmay
affect the clearance of this group of drugs that are substantially
metabolized by CYP2D6, and thus alter the clinical response
to them.
1.2.1 Aripiprazole
Aripiprazole, an arylpiperazine quinolinone derivative, is a
novel atypical antipsychotic drug with D2 and 5-HT1A receptor
agonistic and 5-HT2A antagonistic property indicated for the
treatment of schizophrenia in adults.[150] Aripiprazole is also a
high-affinity partial agonist at 5-HT2A receptors and a low-
affinity agonist at 5-HT2C receptors, and moderate affinity at
a1-adrenoceptors and histamine H1 receptors.[151] The elim-
ination of aripiprazole is mainly mediated through the hepatic
metabolism. Aripiprazole undergoes dehydrogenation, aro-
matic hydroxylation followed by conjugation and N-deal-
kylation (see supplementary figure 28, Supplemental Digital
Content 1). The main active metabolite, dehydroaripiprazole
(OPC-14857with a t½ of 90 hours), has affinity forD2 receptors
and thus has some pharmacological activity similar to that
of the parent drug. The formation of dehydro-aripiprazole
was mainly mediated by CYP2D6 and 3A4. At steady state,
dehydroaripiprazole represents ~40% of aripiprazole AUC in
human plasma. There was a 37-fold interindividual variability
in the concentration/dose ratio for aripiprazole.[152]
Several clinical studies have found that the genotype of
CYP2D6 affects the clearance of aripiprazole.[153-157] In psy-
chiatric patients, the median serum concentration of ar-
ipiprazole was 1.7-fold higher in PMs than in EMs (45.5 vs
26.3 nmol/L/mg and the sum of the serum concentrations of
aripiprazole plus dehydroaripiprazole was 1.5-fold higher in
PMs than in EMs (53.9 vs 37.0 nmol/L/mg).[157] The oral clear-
ance of aripiprazole in healthy Japanese subjects was estimated
to be 0.0645L/h/kg in the group with CYP2D6*1/*1, *1/*2 and*2/*2, but it decreased to 0.0135L/h/kg in the group with
CYP2D6*1/*5, *1/*10, *2/*5, *2/*10, and *2/*41, and
0.0293L/h/kg in the group with CYP2D6*5/*10, *10/*10, and*41/*41.[155] There is a case report where very high plasma
concentrations of aripiprazole were noted in a patient who had
nonfunctional CYP2D6.[158] The systemic exposure to dehy-
droaripiprazole was lower by 30% in IMs than in EMs[153] as
well as 30% lower in PMs than in EMs, whereas the median
concentration/dose ratios of dehydroaripiprazole were similar
in PMs and EMs.[157] However, only three healthy subjects with
the IM phenotype completed the single-dose study by Kubo
et al.,[156] and the AUC of dehydroaripiprazole was higher in
IMs than in EMs in the multiple-dose study conducted by the
same group,[156] reflecting the limited role of CYP2D6 in the
formation of dehydroaripiprazole.
Kim et al.[154] recently investigated the relationship of
CYP2D6 genotype and aripiprazole pharmacokinetics in 80
schizophrenic patients receiving multiple oral doses of aripipra-
zole (10–30mg/day). Covariate analysis showed that CYP2D6
genetic polymorphisms significantly influenced the oral clearance
of aripiprazole and reduced the interindividual variability of oral
clearance from 37.8% (coefficient of variation) to 30.5%. The oral
clearance of aripiprazole in IMs (n= 27) carrying at least one
partially deficient allele was ~60% of that in EMs (n= 53) having
at least one functional allele (*1 or *2).[154] Based on theCYP2D6genotype, the MRs were calculated at 0.20–0.34. However, the
plasma concentration/dose ratio of dehydroaripiprazole was not
affected by the CYP2D6 genotype.[154]
The plasma concentration of aripiprazole was increased by
coadministered itraconazole, and the decrease in oral clearance
was estimated to be 0.0181 L/h/kg. By coadministration of
itraconazole, the oral clearance of aripiprazole in EMs was
decreased by 26.6%, with an even greater decrease (47.3%) in
IMs.[153] Olanzapine, alimemazine, lithium, risperidone injec-
tions, escitalopram or lamotrigine had significant effects on
aripiprazole disposition in psychiatric patients.[159]
These results indicate a role of CYP2D6 in its metabolism
but CYP3A4may be more important for its disposition and the
CYP2D6 phenotype marginally affects the clearance of ar-
ipiprazole. There is no need to adjust the dosage, since its major
metabolite dehydroaripiprazole is pharmacologically active.
1.2.2 Chlorpromazine
Chlorpromazine, a prototype phenothiazine antipsychotic
drug, is used in the treatment of schizophrenia and the manic
phase of bipolar disorder as well as amfetamine-induced
psychoses, but its use today has been largely replaced by the
newer atypical antipsychotics such as olanzapine and quetia-
pine. Chlorpromazine has anticholinergic (M1 and M2), anti-
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dopaminergic (mainly D2, D3 andD5), antiserotonergic (5-HT1
and 5-HT2) and antihistamine (H1) effects as well as some an-
tagonistic activity of adrenergic receptors. Chlorpromazine is
extensively metabolized in the liver via 7-hydroxylation,
N-dealkylation, N-oxidation and S-oxidation, as well as con-
jugation, resulting in more than 100 metabolites with greatly
varying half-lives and pharmacological profiles (see supple-
mentary figure 29, SupplementalDigital Content 1). Among these
pathways, the 7-hydroxylation is a major metabolic pathway of
chlorpromazine in humans.[160] Chlorpromazine is converted to
active 7-hydroxychlorpromazine largely by CYP2D6[161] and
this pathwaywas inhibited by quinidine in EMs of debrisoquine
in vivo.[162] Two other common metabolites areN-didesmethyl-
chlorpromazine and chlorophenothiazine in which the entire
side chain has been removed. Only 7-hydroxychlorpromazine,
promazine, 9-hydroxyresperidone, and a few N-demethylated
metabolites showed pharmacological activities.
In healthy Korean subjects, nonsignificant 1.3- and 1.7-fold
higher chlorpromazine AUC values were observed in in-
dividuals heterozygous and homozygous for CYP2D6*10,respectively, compared with the wild-type[163] It appears
CYP2D6*10 does not significantly alter the pharmacokinetics
of chlorpromazine which is metabolized not only by CYP2D6
but also by CYP1A2 and 4A11.[161]
1.2.3 Haloperidol
Haloperidol is one of the most commonly used anti-
psychotics in the treatment of patients with acute and chronic
schizophrenia.[164,165] Haloperidol undergoes extensive and
complex metabolism involving various CYP isoenzymes
(mainly CYP3A4 and 2D6), with direct glucuronidation being
the predominant elimination pathway and followed by the re-
duction of haloperidol to reduced haloperidol and by CYP-
mediated oxidation. Haloperidol is reduced by cytosolic car-
bonyl reductase to reduced form, which has 10–20% of the
activity of the parent molecule and is further metabolized by
CYP3A4 to a tetrahydropyridine and conjugated by glucur-
onidation and sulphation. Reduced haloperidol is back-
oxidized to haloperidol primarily by CYP3A4 and 2D6 (see
supplementary figure 30, Supplemental Digital Content 1).[166-168]
Haloperidol is N-dealkylated by CYP3A4 and 2D6 to
4-chlorophenyl-4-hydroxypiperidine and p-fluorobenzoyl pro-
pionic acid. Unlike its parent molecule haloperidol, reduced
haloperidol exists as two enantiomeric forms with an asym-
metric chiral centre. Only the S-(-)-enantiomer of reduced
haloperidol is generated from haloperidol by carbonyl re-
ductase in human tissues. Reduced haloperidol also undergoes
N-dealkylation by CYP2D6, 1A2, 2C9, 2B6, 2E1 and 3A4 to 4-
chlorophenyl-4-hydroxypiperidine and 4-(p-fluorophenyl)-4-
hydroxybutyric acid.[166,167] Both haloperidol and reduced
haloperidol are converted to the pyridinium ions via dehydra-
tion. After coadministration of rifampicin (rifampin) in schi-
zophrenic patients, daily trough haloperidol concentrations
rapidly decreased and reached 63% of baseline level by day 3,
41.3% by day 7 and 30% by day 28.[169] In schizophrenic patients,
fluoxetine (a CYP2D6/1A2 inhibitor) significantly increased
the plasma concentrations of haloperidol.[170] Fluvoxamine
(a CYP2D6/1A2 inhibitor) also caused a moderate increase in
the plasma concentrations of haloperidol and its reduced me-
tabolite in patients.[171] These results indicate that CYP2D6
plays a partial role for the disposition of haloperidol but
CYP3A4 is also important for its overall disposition. There is
large interindividual variability in the pharmacokinetics and
the clinical outcome of haloperidol treatment. A therapeutic
range of 14.9 and 45.0 nmol/L for haloperidol has been sug-
gested,[172] and patients with plasma haloperidol concentra-
tions within this range showed significantly better response
than those outside the range.
There was a significant correlation between dextro-
methorphan MRs and plasma haloperidol concentrations,
reduced haloperidol concentrations, and reduced haloper-
idol/haloperidol ratios.[173] A single-dose (2–4mg) study in
healthy Caucasian subjects reported that PMs eliminated ha-
loperidol 2-fold more slowly than EMs (clearance: 1.16 vs
2.49 L/h/kg), with the mean plasma t½ being longer in PMs
(29.4 vs 16.3 hours).[174] The plasma concentrations of reduced
haloperidol from 10 to 72 hours postdose were 2- to 4-fold
higher in PMs than in EMs after a single 2mg or 4mg dose of
haloperidol.[175] A study of eight Caucasian patients showed the
highest plasma concentration of haloperidol and highest D2
receptor occupancy in the sole PM compared with EMs, in-
dicating higher risk of extrapyramidal symptoms.[176] This
study was conducted using relatively low doses of haloperidol
(30–50mg/4 weeks). CYP2D6 appears important for the me-
tabolism of haloperidol at low doses. The formation of reduced
haloperidol from haloperidol seems to be independent of
CYP2D6 activity, and there is a decreased reoxidation of the
reduced metabolite to haloperidol by CYP2D6.
Brockmoller et al.[177] reported a significant correlation be-
tween reduced haloperidol trough concentrations and halo-
peridol total clearance and the number of activeCYP2D6 genes
in a studywith 172German psychiatric patients. This study also
found that the rating for pseudo-parkinsonism induced by
haloperidol was higher in PMs than in EMs; there was a trend
towards lower therapeutic efficacy with an increasing number
of active CYP2D6 genes. Another study in 26 Swedish schizo-
774 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
phrenic patients by Panagiotidis et al.[178] found a significant
correlation between haloperidol plasma concentrations and the
number of active CYP2D6 alleles. However, there was no
correlation between plasma concentrations of haloperidol or
the number of CYP2D6 alleles and the therapeutic outcome or
adverse effects.[178]
Two studies in Japanese schizophrenic patients treated with
haloperidol at a fixed daily dose of 12mg[179,180] have shown a
relationship between increased steady-state haloperidol plasma
concentrations and the presence of a nonfunctionalCYP2D6*10allele. In one study of 67 Japanese inpatients with schizophrenia,
the mean haloperidol concentrations in the patients with no, one
and two *10 alleles were 22.8, 30.1 and 31.2 nmol/L, respectively,and the values for reduced haloperidol were 6.1, 9.5 and
9.9 nmol/L.[180] The mean haloperidol concentrations were sig-
nificantly higher in the patients with one *10 allele than in those
with no *10 alleles, and the mean reduced haloperidol concentra-
tions were significantly higher in the patients with one and two
*10 alleles than in those with no *10 alleles.
In a study with 120 Korean schizophrenic patients,[181] a
relationship between haloperidol concentrations normalized
for the dose of haloperidol and the CYP2D6 genotype (CY-
P2D6*1/*1, *1/*10 and *10/*10) was found in patients receivinghaloperidol <20mg daily but not in patients receiving higher
doses (>20mg). In this study, 60% of individuals with the CY-
P2D6*1/*10 or *10/*10 genotypes (n = 93) required benztropine
(an anticholinergic drug used to reduce the adverse effects of
haloperidol) compared with 35% of EMs (n = 23). All four pa-
tients with a *5 allele (one together with *1 and three with *10)were found to use benztropine. However, there were no sig-
nificant differences between the genotype groups with respect
to the concentrations of reduced haloperidol. In patients re-
ceiving doses of haloperidol >20mg, no differences were found
between the genotype groups for either haloperidol or reduced
haloperidol.[181] These findings demonstrate a clear correlation
between dose-corrected steady-state plasma concentrations
of haloperidol, but not of reduced haloperidol, and the
CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when
doses are <20mg, suggesting involvement of CYP2D6 in the
metabolism of haloperidol at low doses of haloperidol, while
another enzyme, probably CYP3A4, contributes to its meta-
bolism at higher doses.
Healthy Korean subjects with the CYP2D6*10/*10 genotype
showed 81% higher AUC values for haloperidol than subjects
with the CYP2D6*1/*1 genotype (27.6 vs 50.2 ng � h/mL).[182]
When co-treated with itraconazole (a CYP3A4 inhibitor), sub-
jects withCYP2D6*10/*10 showed 3-fold higher AUC values for
haloperidol than placebo-pretreated subjects with the CYP-
2D6*1/*1 genotype (21.7 vs 66.7 ng � h/mL). The CYP2D6*10genotype and itraconazole pretreatment decreased oral clearance
of haloperidol by 24% and 25%, respectively, but without sta-
tistical significance. However, in subjects with the CYP2D6*10genotype who received itraconazole pretreatment, the oral
clearance was significantly decreased to 42% of that of subjects
with the wild-type genotype receiving placebo pretreatment
(4.7 vs 2.0L/h/kg).[182] Although the CYP2D6*10 genotype and
itraconazole pretreatment caused more haloperidol-induced
adverse effects and higher scores for its therapeutic effect, these
did not reach statistical significance. These results indicate that
the moderate effect of the CYP2D6*10 genotype on the phar-
macokinetics and pharmacodynamics of haloperidol can be
augmented by the presence of itraconazole pretreatment.
A steady-state study in Chinese schizophrenic patients
(n= 18) treatedwith oral haloperidol 10mg/day for 2weeks foundsignificant correlations between dextromethorphan MRs and
plasma haloperidol concentrations, reduced haloperidol con-
centrations, and reduced haloperidol/haloperidol ratios.[173]
The authors also reported higher reduced haloperidol con-
centrations and reduced haloperidol/haloperidol ratios in pa-
tients who experienced more extrapyramidal adverse effects
than in other patients without these adverse effects.[173]
However, several other studies have reported that steady-
state haloperidol concentrations tend to be slightly higher in
those with CYP2D6 alleles (e.g. *10 in Japanese and *4 in
Caucasian), causing reduced or nonfunctional enzyme activity,
or even no significant difference.[183-185] Reduced haloperidol
concentrations are more consistently increased in those with
nonfunctional CYP2D6 alleles (e.g. *10 in Japanese), causing
reduced or nonfunctional enzyme activity in schizophrenic
patients.[179,180,183,185] For example, a study in Japanese pa-
tients did not observe any significant difference in plasma ha-
loperidol concentrations between the subjects with no, one and
two *10 alleles.[183] Someya et al.[186] also found no association
of the CYP2D6*10A allele with plasma concentrations of
haloperidol. The study in 111 Japanese patients by Ohnuma
et al.[184] found no significant difference in the plasma con-
centration of haloperidol normalized by dose between the
groups classified by CYP2D6*10A and *2 genotypes, even
in patients whose daily doses were <20mg (n = 90). Patients
carrying duplicated CYP2D6 genes (n = 6) did not show sig-
nificant differences in plasma concentrations of haloperidol
compared with subjects who had no duplicated genes.[184]
Patients with gene duplication had slightly higher daily doses
of haloperidol (16mg; range 3–30mg) than those without
duplication (10mg; range 1–45mg), but this did not reach
statistical significance.
Pharmacogenetics of CYP2D6 775
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
These conflicting results suggest that CYP2D6 plays a role in
the disposition of haloperidol and reduced haloperidol in
Asians, but that other enzymes (e.g. CYP1A2) may be more
important in determining the overall metabolism of haloper-
idol. The decrease in CYP2D6 enzyme activity caused by CY-
P2D6*10A might not be sufficient to affect the clinical plasma
concentration of haloperidol, while the nonfunctional *4 allele
may cause significant changes in plasma concentrations of
haloperidol. The high-affinity, low-capacity CYP2D6 appears
to play an important role at low concentrations/doses of ha-loperidol, while the low-affinity, high-capacity CYP3A4/1A2 is
more important with higher doses of haloperidol and long-term
maintenance treatment. The influence of decreased enzyme
activity by the CYP2D6*10A allele on the plasma concentra-
tion of haloperidol is yet to be confirmed by studies of larger
cohorts of patients. The complexity of haloperidol pharmaco-
kinetics compromises the clinical value of knowledge of the
CYP2D6 genotype in the determination of dosage and regimen.
Further studies are warranted to explore the clinical impact of
CYP2D6 polymorphisms on haloperidol therapy.
1.2.4 Perphenazine
Perphenazine, a piperazinyl phenothiazine, is a typical anti-
psychotic drug used in the treatment of schizophrenia and
manic phases of bipolar disorder.[187] Perphenazine is 10–15
times as potent as chlorpromazine but it causes high incidences
of early and late extrapyramidal adverse effects and tardive
dyskinesia.[187] Perphenazine is extensively metabolized in the
liver to a number of metabolites, mainly by sulfoxidation, ring
hydroxylation at position 7 followed by glucuronidation, and
N-dealkylation leading to loss of the hydroxyethyl group.
Minor metabolic pathways may be N-oxidation and direct
glucuronidation of the primary alcohol group. Perphenazine is
primarily metabolized by CYP2D6 to N-dealkylated perphe-
nazine, perphenazine sulfoxide and 7-hydroxyperphenazine
(see supplementary figure 31, Supplemental Digital Content 1),
with the pharmacological activity of the latter metabolite being
70% of that of the parent drug.[188] Other metabolites are
considered to be inactive. CYP2D6, 1A2, 3A4 and 2C19 are the
most important contributors to N-dealkylation. N-deal-
kylperphenazine is usually present in vivo at concentrations
1.5- to 2-fold higher than those of the parent drug. In in vitro
binding studies, N-dealkylperphenazine showed a higher affi-
nity for 5-HT2A receptors than for D2 receptors to an extent
comparable to that of some atypical antipsychotic agents.
The disposition of perphenazine cosegregated with
CYP2D6-mediated debrisoquine hydroxylation.[189] A 4-fold
higher AUC of perphenazine in PMs following a single dose
was observed compared with EMs.[190] Similarly, steady-state
studies have demonstrated a 2-fold highermedianAUC[191] and
a 3-fold decrease in the clearance of perphenazine[192] in PMs. A
recent study in nonsmoking healthy male Chinese-Canadian
subjects reported a 2.9-fold higher AUC of perphenazine
in carriers of homozygous CYP2D6*10 than in those carrying
the CYP2D6*1 allele.[193] In this study, individuals who were
homozygous for CYP2D6*10 were found to have significantly
reduced prolactin production and tissue response. The asso-
ciation between the prolactin response to perphenazine and
the CYP2D6 genotype was also observed in another study in
Swedish patients.[194] In contrast to hyperprolactinaemia,
which is a common adverse effect of first-generation anti-
psychotics, caused by antagonism of dopaminergic neuro-
transmission in the pituitary,[195-199] the prolactin response
appears to be blunted in subjects who are homozygous for
CYP2D6*10. A possible explanation is that CYP2D6 genetic
polymorphism may potentially influence pharmacodynamic
tissue sensitivity in the pituitary, presumably through disposi-
tion of an endogenous substrate (e.g. 5-methoxytryptamine,
which can be converted to serotonin by CYP2D6 in the
brain[200]).
Paroxetine, a potent CYP2D6 inhibitor, increased theAUCof
perphenazine 7-fold in EMs, which was associated with a sig-
nificant increase in CNS symptoms, including sedation, extra-
pyramidal symptoms and psychomotor performance.[201] In
elderly patients with dementia, perphenazine 0.05–0.1mg/kg/dayled to improved psychotic symptoms overall without any differ-
ence between EMs and PMs. However, PMs had significantly
more adverse effects (primarily extrapyramidal and sedation)
early in treatment, which became similar in both phenotypes by
day 17 of dosing.[202]
1.2.5 Risperidone
Risperidone is an atypical antipsychotic used for the treat-
ment of positive and negative symptoms of schizo-
phrenia.[145,203] Risperidone is a 5-HT2A and D2 receptor
antagonist, which acts particularly on the negative symptoms
of schizophrenia and has a lower potential to induce extra-
pyramidal adverse effects than classical antipsychotics.[204] It
also acts on H1 receptors and a1- and a2- adrenoceptors. Ris-
peridone is mainly metabolized by 9-hydroxylation of the tet-
rahydropyridopyrimidinone ring (31% of the dose) and, to a
lesser extent, by N-dealkylation and 7-hydroxylation.[205] Oxi-
dative N-dealkylation results in two acidic metabolites, one
derived from risperidone itself and the other from 9-hydro-
xyrisperidone. Risperidone is converted to 9-hydroxyrisperidone
byCYP2D6and 3A4 (see supplementary figure 32, Supplemental
776 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
Digital Content 1).[206] The latter is further metabolized by N-
dealkylation, possibly by CYP3A4.[207,208] 9-Hydroxyrisperidone
is the major metabolite in plasma, and it is equipotent with the
parent drug in dopamine receptor affinity and hence contributes
to the overall therapeutic effect of risperidone.[209] In one study,
unchanged risperidone was mainly excreted in the urine and ac-
counted for 30%, 11% and 4% of the administered dose in PMs,
IMs andEMs, respectively. 9-Hydroxyrisperidone excreted in the
urine accounted for 8%, 22% and 32% of the administered dose in
PMs, IMs andEMs, respectively.After 4 weeks of treatment with
paroxetine (a CYP2D6 inhibitor), the sum of the concentrations
of risperidone and 9-hydroxyrisperidone increased significantly
by 45% over baseline.[210] Another study in 218 schizophrenic
patients found that there were higher plasma concentrations of
risperidone but without any change in the plasma concentration
of 9-hydroxyrisperidone when one or more CYP2D6 inhibitor
was coadministered.[211] A possible explanation would be that
9-hydroxylation represents the major pathway of elimination of
risperidone, and similar concentrations of 9-hydroxy-metabolite
are found at steady state with and without reduced CYP2D6
activity. Since the pharmacological difference and distribution
in the CNS between the parent compound and the 9-hydroxy-
metabolite are unclear, the clinical relevance of the CYP2D6
polymorphism is yet to be determined.
The ratio of risperidone to 9-hydroxyrisperidone concentra-
tions has been reported as <1 in EMs and >1 in PMs among
various ethnic groups, but the sum of the active moieties was
comparable in EMs and PMs.[212-216] In the extreme, UMs have
very low ratios of risperidone to 9-hydroxyrisperidone.[136,217] A
study in 37 Italian schizophrenic patients revealed that the med-
ian steady-state plasma concentrations of risperidone normalized
for dose were 0.6, 1.1, 9.7 and 17.4nmol/L/mg in UMs (n= 3),
homozygous EMs (n= 16), heterozygous EMs (n= 15) and PMs
(n= 3), respectively, with statistically significant differences be-
tween PMs and the other genotypes.[212] The concentration of
9-hydroxyrisperidone did not correlate with the CYP2D6 geno-
type. The risperidone/9-hydroxyrisperidone ratio was associated
with theCYP2D6genotype,with the highest ratios being found in
PMs (median 0.79). Heterozygous EMs also had significantly
higher ratios than homozygous EMs (median value 0.23 vs 0.04)
or UMs (median 0.03).[212] No significant differences were found
in the sum of the plasma concentrations of risperidone and 9-
hydroxyrisperidone between the genotype groups. In a study of
82 Korean schizophrenic patients, Roh et al.[216] found that the
median concentrations of risperidone normalized for dose in the
CYP2D6*1/*1, *1/*10 and *10/*10 groups were 1.7, 2.6
and 6.7 nmol/L/mg, respectively. For 9-hydroxyriperidone, the
corresponding median concentrations were 13.1, 11.9 and
13.6 nmol/L/mg, respectively, with no significant difference be-
tween the genotypes. The medians of the ratios between risper-
idone and 9-hydroxyrisperidone concentrations were 0.13, 0.28
and 0.46nmol/L/mg in the *1/*1, *1/*10 and *10/*10 genotypes
(p< 0.05).
The CYP2D6 phenotype status also affects the extent of drug
interactions when a CYP2D6 inhibitor is coadministered with
risperidone. The AUCs of risperidone increased from 83.1 and
398.3 ng� h/mL (monotherapy) to 345.1 and 514.0ng � h/mL
when coadministered with fluoxetine in EMs and PMs, respec-
tively.[213] The AUC of the active moiety (risperidone plus
9-hydroxyrisperidone) increased from470.0 to 663.0ng � h/mL in
EMs and from 576.3 to 788.0 ng � h/mL in PMs. In EMs, the
AUCof 9-hydroxyrisperidone remained similar (monotherapy vs
combination therapy: 386.8 vs 317.7 ng � h/mL), whereas it sig-
nificantly increased in PMs (178.3 vs 274.0 ng� h/mL).
A few studies have investigated whether the CYP2D6 phe-
notype status is associated with adverse reactions to risper-
idone. A large cross-sectional study (n = 500) in schizophrenic
patients in southern Germany reported a 3-fold increased risk
of moderate to severe adverse effects in PMs compared with
EMs.[136] However, PMs constituted only a small proportion
(16%) of all patients with adverse effects, and only 9% of PMs
discontinued risperidone because of adverse effects in this
study. Another study in schizophrenic patients in the US re-
ported a 3.1-fold higher risk of moderate to severe adverse
effects in PMs than in EMs.[218] There was no correlation be-
tween the serum concentration of the active moiety and the
adverse effects of risperidone.[214]
The above data demonstrate a clear gene-concentration ef-
fect for risperidone, due to the major role of CYP2D6 in its
metabolism and activation. However, this is of minor clinical
significance, as there is a comparable sum of risperidone and
9-hydroxyrisperidone in PMs and EMs, and both the parent
and the primary active metabolite formed by CYP2D6 show
similar activity. Genotyping/phenotyping of CYP2D6 is help-
ful in identifying individuals at increased risk of toxicity but is
unlikely to sort out responders and nonresponders. In UMs, a
dosage increase may be required to achieve therapeutically
relevant concentrations.
1.2.6 Thioridazine
CYP2D6 and 3A4 convert thioridazine to mesoridazine,[219]
which correlates weakly with the debrisoquine MR,[220,221]
whereas the subsequent metabolite sulforidazine (thioridazine
2-sulfone) does not seem to be reliant on CYP2D6 (see supple-
mentary figure 33, Supplemental Digital Content 1).[222] There
was a weak correlation between the corrected QT interval and
Pharmacogenetics of CYP2D6 777
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
thioridazine plasma concentrations, the debrisoquine MR and
thioridazine/mesoridazine concentrations.[223] The metabolites
seem to have activity equal to (sulforidazine) or greater than
(mesoridazine) that of the parent, whereas a further ring sulfoxide
(thioridazine 5-sulfoxide) produced from thioridazinemay be less
active as an antipsychotic but more arrhythmogenic. After a
single dose, the sum of plasma concentrations of the active
moieties (thioridazine, mesoridazine plus sulforidazine) was
~1.4-fold higher in PMs, largely owing to a 4.5-fold increase in the
thioridazine concentration itself.[224] Consistent with this, the
dose-corrected median steady-state plasma thioridazine con-
centrations were 3.8- and 1.8-fold higher in the presence of no or
one active CYP2D6 alleles, respectively, compared with two
active alleles. The median concentrations of mesoridazine and
sulforidazine were no different.[221]
1.2.7 Zuclopenthixol
Zuclopenthixol, a thioxanthene derivative used in the
treatment of schizophrenia, has high affinity for both D1 and
D2 receptors, a1-adrenoceptors and 5-HT2 receptors.[225] It has
weak H1 receptor blocking activity and lower affinity for
muscarinic cholinergic and a2-adrenoceptors. The pharmaco-
kinetics of zuclopenthixol appear linear over the dosage
range investigated. Zuclopenthixol is metabolized mainly by
sulfoxidation, side chain N-dealkylation and glucuronidation
(see supplementary figure 34, Supplemental Digital Content 1).
The metabolites are devoid of pharmacological activity.
Zuclopenthixol sulfoxidation and N-dealkylation are mainly
metabolized by CYP2D6 and other enzymes.[226]
The clearance of zuclopenthixol cosegregated with debriso-
quine hydroxylation in humans,[189,226] indicating the involve-
ment of CYP2D6 in the metabolism of zuclopenthixol. In
healthy subjects, a 1.9-fold higher AUC of zuclopenthixol was
observed in PMs than in EMs (n = 6 for each phenotype) after
a single dose of zuclopenthixol (6 or 10mg).[226] The plasma
t½ was significantly longer in PMs than in EMs (29.9 vs
17.6 hours) and the total oral plasma clearance was lower in
PMs than in EMs (0.78 vs 2.12 L/h/kg).[226]
Linnet and Wiborg[227] reported that the median steady-state
plasmaconcentration of zuclopenthixol normalized for dose in 12
psychiatric patients who were PMs was 60% higher than that in
EMs (2.0 vs 1.25 nmol/L/mg) but was close to that of EMs re-
ceiving potentially interacting drugs that inhibit CYP2D6 (2.0 vs
1.80nmol/L/mg).Another study in 52 schizophrenic patients on a
maintenance dosage of zuclopenthixol at 100–400mg/4 weeks
found that the median steady-state plasma concentrations of
zuclopenthixol were 1.6- and 1.4-fold higher in PMs (n= 4) and in
heterozygous EMs (n= 13), respectively, than in homozygous
EMs (n= 35).[228] The nonfunctional CYP2D6*3 and *4 alleles
tended to be more frequent in patients with neurological adverse
effects. There were odds ratios of 2.3 for development of par-
kinsonism and 1.7 for tardive dyskinesia in an individual with at
least one nonfunctional CYP2D6 allele, but these findings were
not statistically significant.[228] In addition, a steady-state study in
36 Swedish schizophrenic patients reported that the clearance
rates of zuclopenthixol were 2.2- and 1.5-fold higher in homo-
zygous and heterozygous EMs, respectively, than in PMs.[192]
These findings demonstrate a gene-concentration effect for
zuclopenthixol, but the evidence for a gene-response relation-
ship is lacking.Genotyping/phenotypingmay be used to predict
the plasma concentrations of zuclopenthixol.
1.2.8 Miscellaneous Antipsychotics
Clozapine, olanzapine and quetiapine are extensively meta-
bolized by CYP1A2 and 3A, with a minor contribution from
CYP2D6.[229] CYP1A2, 3A4, 2C9, 2C19 and 2D6 have been
shown toN-demethylate clozapine to norclozapine, whileN-oxide
formation was catalysed by CYP3A4, 1A2 and flavin-containing
monooxygenase 3 (FMO3) [for themetabolic scheme of clozapine,
see supplementary figure 35, Supplemental Digital Content 1].[230]
The estimated contributions of CYP1A2, 2C19, 3A4, 2C9 and
2D6 amounted to 30%, 24%, 22%, 12% and 6%, respectively,
with regard to N-demethylation of clozapine.[230] CYP2D6
might play a role in the formation of metabolites other than N-
desmethylclozapine (norclozapine) and theN-oxide. Clozapine
is also hydroxylated at ring positions 6, 7, 8 and 9, followed by
conjugation.[231] Introduction of OH with removal of Cl at C8
was a major metabolic pathway, resulting in 8-OH-clozapine.
C7 hydroxylation was another quantitatively important pathway,
resulting in 7-OH-desmethylclozapine O-sulphate as a major
metabolite in human urine. Clozapine is also glucuronidated by
UGT1A4 to the quaternary N+-glucuronide and 5-N-glucur-
onide, which can be detected in the patient’s urine.[232] It can be
expected that the CYP2D6 phenotype status would not signifi-
cantly change the pharmacokinetics of these antipsychotics.
The CYP2D6 phenotype did not correlate with the AUC of
olanzapine after a single dose of 7.5mg in healthy subjects.[233]
A similar negative result was observed at steady state in psy-
chiatric patients.[234] Clozapine and N-desmethylclozapine
concentration ratios were not related to the CYP2D6 genotype
in patients[235] and the CYP2D6 genotype did not affect clo-
zapine-induced agranulocytosis.[236] The mean increase in the
R-methadone concentration/dose ratios with coadministration
of quetiapine were 7%, 21% and 30% in PMs, heterozygous
EMs and homozygous EMs, respectively.[237] Thus, there is a
clear lack of a gene-concentration effect.
778 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
A study in 131 Slovenian schizophrenic patients on main-
tenance therapy with haloperidol, fluphenazine, zuclopenthixol
or risperidone reported no significant differences in psycho-
pathological and extrapyramidal symptoms with regard to the
CYP2D6 genotype, except that PMs scored significantly higher
on the negative subscale for psychopathological symptoms.[238]
However, a pilot study of 100 psychiatric inpatients showed a
trend for increasing adverse reactions with CYP2D6 substrate
drugs (e.g. haloperidol, perphenazine, risperidone and tricyclic
antidepressants) as one moved from the UM group to the PM
group and a higher cost of treating these two groups.[239] It ap-
pears that the CYP2D6 genotype might be a factor contributing
to the persistent negative symptoms of schizophrenia but not a
major factor determining the susceptibility to antipsychotic-in-
duced extrapyramidal adverse effects in patients on maintenance
therapy with antipsychotics that are mainly CYP2D6 substrates.
1.2.9 Summary of Antipsychotics
All of the above results indicate significant relationships
between the CYP2D6 genotype and steady-state concentra-
tions of perphenazine, zuclopenthixol, risperidone and halo-
peridol.[240,241] Other CYP enzymes, especially CYP3A4 and
1A2, also contribute to interindividual variability in the clear-
ance of many antipsychotics and thus reduce the magnitude of
such relationships. For most antipsychotics, the relative con-
tributions of the different CYP isoenzymes at therapeutic drug
concentrations remain to be determined. PMs of substrates of
CYP2D6 appear to bemore prone to oversedation and possibly
parkinsonism during treatment with classical antipsychotics,
but the relationship is not conclusive.
In addition, findings regarding the relationships between the
CYP2D6 genotype and parkinsonism or tardive dyskinesia
with traditional antipsychotics have been conflicting, probably
due to small sample size, inclusion of antipsychotics with
variable CYP2D6 metabolism, and co-medication. A recent
meta-analysis showed a significant 1.4-fold increased risk of
tardive dyskinesia in PMs.[242] Based on these available data,
phenotyping and/or genotyping for CYP2D6 may be used as a
complement to determination of plasma drug concentrations
when aberrant metabolic capacity (poor or ultrarapid) of
CYP2D6 substrates is suspected. CYP2D6 phenotyping and
genotyping appear to be useful in predicting the steady-state
concentrations of some classical antipsychotic drugs, but their
usefulness in predicting clinical effects must be explored.
Therapeutic drugmonitoring has been strongly recommended
for many antipsychotics including haloperidol, chlorpromazine,
fluphenazine, perphenazine, risperidone and thioridazine, which
are all metabolized by CYP2D6.[243] Clozapine and olanzapine
are also included in this list, althoughCYP2D6plays aminor role
in their overall metabolic elimination. It is possible to merge both
therapeutic drug monitoring and pharmacogenetic testing for
CYP2D6 in clinical practice.
1.3 Centrally Acting Cholinesterase Inhibitors
Centrally acting cholinesterase inhibitors are the first-line
agents used in the treatment of Alzheimer’s disease and include
tacrine, donepezil, galantamine and rivastigmine.[244] Rivas-
tigmine is almost entirely metabolized by sulphate conjugation.
Tacrine,[245] donepezil[246] and galantamine[247] are metabolized
by CYP2D6 to some extent. However, CYP1A2 and 3A4 play a
more important role in their metabolism than CYP2D6,[244]
and thus the impact of CYP2D6 polymorphisms on their
clearance would be minor.
1.3.1 Donepezil
Donepezil is a reversible and selective acetylcholinesterase
inhibitor that exhibits high specificity for centrally active choli-
nesterase and is widely used in the treatment of mild to moderate
Alzheimer’s disease.[248,249] Since donepezil is >1250-fold more
selective for acetylcholinesterase than for butyrylcholinesterase
(an enzyme primarily acting at the periphery of the body),
donepezil is associated with a low incidence of acetylcholine-
mediated adverse events.[250] Donepezil displays linear pharmaco-
kinetics in the therapeutic range of doses. Donepezil has three
major metabolic pathways in humans: O-dealkylation and
hydroxylation to metabolites M1 and M2, with subsequent
glucuronidation to metabolites M11 and M12; hydrolysis to
metabolite M4; and N-oxidation to metabolite M6 (see supple-
mentary figure 36, Supplemental Digital Content 1).[251] In hu-
man urine, the major metabolite is M4, followed by the
glucuronidated conjugates M11 and M12.[251] In human liver
microsomes, M4 is formed mainly by CYP3A4 and to a lesser
extent by CYP2C9 via N-dealkylation, while M1 and M2 are
formedbyCYP2D6and 3A4.[246]Allmetabolites of donepezil are
inactive, with the exception of 6-O-desmethyldonepezil.
A clinical steady-state study in 42 patients of Caucasian
ethnicity from Italy demonstrated that UM patients (n = 2) had
lower plasma concentrations of donepezil than EM patients
(n = 40) and showed no clinical improvement.[249] Heterozygous
EMs had higher donepezil concentrations and a better clinical
response than homozygous EMs. The median concentrations
corrected for the dose and bodyweight of donepezil in UMs,
homozygous EMs and heterozygous EMs were 0.13, 0.33 and
0.41 ng/mL/mg/kg, respectively, but the differences did not
reach statistical significance. No PMs were found in this study.
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In patients treated with a multifactorial therapy, including
cholinesterase inhibitors (e.g. donepezil), the best responders
are CYP2D6-related EMs and IMs, and the poorest responders
were PMs and UMs.[252] In a recent prospective cohort study in
127 patients with mild to moderate Alzheimer disease treated
with donepezil 5–10mg/day for 6 months, there was a sig-
nificantly higher frequency of the -1584C>G (rs1080985) mu-
tation of CYP2D6 in nonresponders than in responders (58.7%vs 34.8%; p= 0.013).[253] This may be due to lower plasma drug
levels since the presence of the G allele was associated with
higher enzyme activity and drug metabolism.[254] These results
suggest that the CYP2D6 polymorphism affects donepezil
metabolism and the therapeutic outcome. The PM phenotype
could predispose patients to higher-than-average plasma con-
centrations of donepezil, with an increased risk of adverse
drug reactions, leading to early discontinuation of treatment.
Knowledge of a patient’s CYP2D6 genotype/phenotype, to-gether with donepezil concentration measurements, might
be useful in the context of improving the clinical efficacy of
donepezil treatment.
1.3.2 Galantamine
Galantamine is a tertiary alkaloid obtained synthetically or
extracted from the bulbs and flowers of several species of the
Amaryllidsceae family.Galantamine has a significant therapeutic
effect in themanagement of patientswithAlzheimer’s disease.[255]
The major route of metabolism for galantamine is through the
liver, accounting for approximately 75% of the total elimination
of galantamine.[256] Galantamine is metabolized by CYP iso-
enzymes, glucuronidated and excreted unchanged in the urine.
The major metabolic pathways of galantamine include glucur-
onidation, O-demethylation, N-demethylation, N-oxidation and
epimerization (see supplementary figure 37, SupplementalDigital
Content 1). Epimerization may occur first, but it is also likely to
occur after glucuronidation, O-demethylation, N-demethylation
andN-oxidation. In vitro studies have shown that CYP2D6 plays
a major role in galantamine O-demethylation,[247] whereas
CYP3A4 catalyses the N-oxidation of galantamine. O-demethy-
lgalanthamine is 10-fold more selective than galantamine for the
inhibition of acetylcholinesterase versus butyrylcholinesterase.
In a study of four healthy subjects, the pharmacokinetic
parameters of galantamine in PMs were similar to those seen in
EMs after a single oral dose of galantamine.[257] However, there
was a marked difference in the metabolism of galantamine
between PMs and EMs. In EMs, six metabolites resulting from
O-demethylation (metabolites 2, 3, 6, 20, 21 and 23) represented
>33% of the dose, whereas these metabolites amounted to only
5% of the dose in PMs.[257] The lower level of excretion of
metabolites formed by O-demethylation in PMs was compen-
sated for primarily by higher levels of unchanged galantamine
and the N-oxide of galantamine (M10) and, to a lesser extent,
by higher levels of the glucuronide of unchanged galantamine
(M5), N-desmethylgalantamine (M8), N-desmethyl-epiga-
lantamine (M16), the N-oxide of epigalantamine (M17) and
epigalantamine (M13). The glucuronide of O-desmethylga-
lantamine represented up to 19% of the plasma radioactivity in
EMs but could not be detected in PMs.[257] This difference is
thought to be of minor clinically relevance, since it neither in-
fluences the plasma concentrations of galantamine or any
pharmacologically active metabolites nor affects the rate of
excretion of galantamine and its metabolites in urine and fae-
ces. These results do not demonstrate a gene-dose/concentra-tion effect on galantamine, and thus adjustment the dosage
based on the CYP2D6 phenotype is not recommended. The
results support an important role of CYP2D6 in O-demethy-
lation of galantamine.
1.4 Drugs for the Treatment of
Attention-Deficit/Hyperactivity Disorder
1.4.1 Atomoxetine
Atomoxetine is a nonstimulant, highly selective nor-
epinephrine reuptake inhibitor approved by the US FDA for the
treatment of attention-deficit/hyperactivity disorder in children,
adolescents and adults.[258,259] In humans, atomoxetine is ex-
tensively metabolized via aromatic ring hydroxylation, benzylic
oxidation and N-demethylation (see supplementary figure 38,
Supplemental Digital Content 1). SubsequentO-glucuronidation
of the ring-hydroxylated metabolites is the only phase II meta-
bolic pathway to participate in the conjugation of the hydro-
xylated metabolites. Atomoxetine is predominantly metabolized
by CYP2D6 to 4-hydroxyatomoxetine (>80% in EMs), but
multiple other CYP isoenzymes including CYP2C19, 3A, 1A2,
2A6 and 2E1 also form 4-hydroxyatomoxetine at a 475-fold
slower rate.[260] The activity of 4-hydroxyatomoxetine is
similar to that of the parent drug. In one study, liver microsomes
from EMs had an intrinsic clearance (CLint) value of
103mL/min/mg for the formation of 4-hydroxyatomoxetine;
however, microsomes from PMs exhibited a CLint value of only
0.2mL/min/mg.[260] This has provided an explanation for the bi-
modal distribution of the clearance of atomoxetine in healthy
subjects after single and multiple dosing.[261] This study also
found that 4-hydroxyatomoxetine was the major oxidative me-
tabolite in both PMs and EMs, but its formation was greatly
decreased in PMs. Individuals lacking CYP2D6 activity have
slower clearance that results in higher steady-state plasma con-
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centrations of atomoxetine and N-desmethylatomoxetine than
those seen in EMs. In one study, paroxetine (a CYP2D6 in-
hibitor) increased the plasma concentrations and AUC values of
atomoxetine by 3- and 6.5- fold, respectively.[262] This was ac-
companied with increased N-desmethylatomoxetine and de-
creased 4-hydroxyatomoxetine concentrations. Healthy EMs
receiving paroxetine had greater increases in heart rate than those
receiving atomoxetine alone.
Sauer et al.[263] investigated the effect of the CYP2D6 poly-
morphism on the overall disposition of a 20mg dose of ato-
moxetine in PMs (n= 3) and EMs (n= 4) at steady state. The
biotransformation of atomoxetine was similar in PMs and EMs,
involving aromatic ring hydroxylation, benzylic oxidation and
N-demethylation with no CYP2D6 phenotype-specific metabo-
lites. The primary oxidative metabolite of atomoxetine was
4-hydroxyatomoxetine, which was subsequently conjugated to
4-hydroxyatomoxetine-O-glucuronide and excreted in the urine
and faeces. The AUC of atomoxetine was 4-fold higher in PMs
than in EMs, and the mean t½ was longer (18 vs 62 hours).[263]
The Cmax of atomoxetine was almost 6-fold higher in PMs than
in EMs. Oral clearance in PMs was about 25% of that in
EMs (0.0357 vs 0.373L/h/kg). Only EMs had measurable 4-
hydroxyatomoxetine concentrations. The plasma Cmax of
N-desmethylatomoxetine was almost 40-fold higher in PMs than
in EMs. The t½ of N-desmethylatomoxetine was approximately
9 hours in EMs and 33 hours in PMs. The mean t½ of 4-hydro-
xyatomoxetine-O-glucuronide was approximately 7 hours in
EMs and 19 hours in PMs. The amount of N-desmethylato-
moxetine- and 2-hydroxymethylatomoxetine-derived metabo-
lites was greater in PMs (22% of the dose) than in EMs (3% of the
dose). Atomoxetine (t½ 5 hours) and 4-hydroxyatomoxetine-O-
glucuronide (t½ 7 hours, ~67%) were the principal circulating
species in EMs, whereas atomoxetine (t½ 20 hours) and N-des-
methylatomoxetine (t½ 33 hours) were the principal circulating
species in PMs. The high plasma concentrations of N-des-
methylatomoxetine in PMs are due not to enhanced production
of N-desmethylatomoxetine but, rather, to its slow systemic
clearance. Following its formation, N-desmethylatomoxetine
must undergo hydroxylation and subsequent O-glucuronidation
prior to its excretion. This hydroxylation appears to be mediated
by CYP2D6 and, therefore, is slower in PMs, resulting in accu-
mulation of N-desmethylatomoxetine in the plasma. These
results demonstrate a clear effect of the CYP2D6 phenotype on
the formation of 4-hydroxyatomoxetine.
In healthy Chinese subjects, homozygous CYP2D6*10 sub-
jects had 50% lower clearance of atomoxetine than other EM
subjects, resulting in 2-fold higher plasma concentrations.[264] The
CYP2D6.10 expressed in insect cells showed 11-fold lower CLint
towards atomoxetine 4-hydroxylation compared with the wild-
type enzyme (0.6 vs 6.99mL/min/pmol CYP).[265]
In children and adolescent patients with attention-deficit/hyperactivity disorder treated with atomoxetine, PMs had
markedly greater reductions in mean symptom severity scores
than EMs.[266] PMs had greater increases in heart rate and dia-
stolic blood pressure and smaller increases in weight than EMs.
Several adverse events, including decreased appetite and tremor,
were more frequent in PMs.[266] These results suggest that PMs
receiving atomoxetine at doses up to 1.8mg/kg/day are likely to
have greater efficacy, greater increases in cardiovascular tone,
and some differences in tolerability compared with EMs.
Trzepacz et al.[267] investigated whether the CYP2D6 geno-
type was associated with the dosage of atomoxetine in children
and adolescents with attention-deficit/hyperactivity disorder.
Patients were evaluated weekly up to 10 weeks, and doses were
titrated for efficacy and tolerability at the discretion of the
physicians (maximum 1.8mg/kg/day). The dose of atomoxetine
was 0.1mg/kg/day lower in PMs (n = 87) than in EMs
(n = 1239). PMs demonstrated marginally better efficacy in
terms of symptoms but had comparable safety profiles, except
for a 4.0 beats/min greater increase in the pulse rate and a 1.0 kg
greater weight loss.[267] The discontinuation rate due to adverse
effects in paediatric patients receiving at least 1.2mg/kg/daywas similar (~3%) in EMs and PMs. The authors suggest that
genotyping is unnecessary during routine clinical management
with atomoxetine, since physicians can adjust the dosage to
achieve comparable efficacy and safety in all individual patients
without knowledge of the CYP2D6 genotype/phenotype.In a clinical study of patients with depression (n = 297), the
safety and tolerability of atomoxetine in PMs was no different
from that in EMs,[268] despite greater exposure observed in PMs
at a comparable dose. The most common adverse events ob-
served in adults are dry mouth, insomnia, nausea, decreased
appetite, constipation, urinary retention or difficulties with
micturition, erectile disturbance, dysmenorrhoea, dizziness and
decreased libido.[269] Another study in Latino (n = 108) and
Caucasian (n = 1090) paediatric patients did not note significant
differences in the incidence of common adverse effects of ato-
moxetine between the two ethnic groups,[270] although there
was a significantly higher frequency of PMs among Caucasians
than among Latinos. However, Caucasian patients experienced
significantly more abdominal and throat pain, whereas Latinos
reported more decreased appetite and dizziness.
These findings indicate that the bimodal distribution of
atomoxetine clearance observed in vivo is due to the primary
involvement of polymorphic CYP2D6 in the formation of the
major metabolite of atomoxetine, 4-hydroxyatomoxetine. The
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formation of N-desmethylatomoxetine, a minor route of ato-
moxetine metabolism, is mediated primarily by CYP2C19.
There is a clear gene-dose effect for atomoxetine. However, the
CYP2D6 phenotype does not affect the adverse reactions to
atomoxetine. There are preliminary data only on the impact of
the CYP2D6 phenotype/genotype on the response to atomox-
etine. Further studies are warranted to investigate the asso-
ciation between the CYP2D6 genotype/phenotype and the
efficacy and adverse effects of atomoxetine.
1.5 Drugs for the Treatment of Senile Dementia
1.5.1 Nicergoline
Nicergoline is an ergot derivative currently used in the treat-
ment of senile dementia and other disorders with vascular origin,
such as Raynaud’s disease and vascular migraine.[271,272] Ni-
cergoline has been found to reduce vascular resistance and
increase arterial blood flow in the brain by inhibiting a1-adre-noceptors, enhance cholinergic and catecholaminergic neuro-
transmitter function, inhibit platelet aggregation and improve
the utilization of oxygen and glucose metabolism in CNS
neurons.[271] Nicergoline is rapidly hydrolysed to an alcohol de-
rivative, 1-methyl-10a-methoxy-9,10-dihydrolysergol (MMDL,
i.e. lumilysergol), which is furtherN-demethylated by CYP2D6
to 10a-methoxy-9,10-dihydrolysergol (MDL) or hydroxylated
to 1-OH-MMDL (see supplementary figure 39, Supplemental
Digital Content 1).[273] MDL has a pharmacological profile
similar to that of nicergoline. In a study of healthy subjects, the
plasma concentrations ofMDLweremuch higher than those of
MMDL, while nicergoline was undetected by conventional
methods. Following oral administration of nicergoline 30mg,
the Cmax of MMDL (21 ng/mL) and MDL (41 ng/mL) were
reached within 1 and 4 hours, respectively. However, higher
plasma concentrations of MMDL than those of MDL have
been noted in about 5% of subjects, suggesting impaired
N-demethylation of MMDL in these individuals.
A further study in healthy subjects found that the AUC of
MDL was 2267 nmol � h/L in EMs (n = 10), but this metabolite
was undetectable in PMs of substrates of CYP2D6 who were
not PMs of substrates of CYP2C19 (n = 5). However, the AUC
of MMDL was 65.7-fold higher in PMs of substrates of
CYP2D6 than in EMs (9471 vs 144 nmol � h/L).[274] This
indicates that the formation of MDL from MMDL via N-
demethylation in the metabolism of nicergoline is largely by
polymorphic CYP2D6, while CYP2C19 does not play a role in
its metabolism. However, since it is unclear whether MMDL
contributes to the clinical efficacy of nicergoline, the impact
of CYP2D6 polymorphisms on the pharmacokinetics and
pharmacodynamics of nicergoline remains to be determined.
1.6 Antimuscarinic Drugs
1.6.1 Tolterodine
Tolterodine is a relatively new antimuscarinic drug that is
used to treat urinary incontinence and other symptoms asso-
ciated with overactive bladder.[275] Tolterodine acts onM1,M2,
M3, M4 and M5 subtypes of muscarinic receptors. Following
oral administration, tolterodine is rapidly absorbed from the
gastrointestinal tract and exhibits extensive first-pass metabo-
lism. In humans, about 80% of an administered oral dose of
tolterodine is excreted in the urine, the major metabolites being
the 5-carboxylic acids of tolterodine, N-dealkylated tolter-
odine, and their glucuronides. Less than 1% of the parent
compound is excreted unchanged. Tolterodine is mainly oxi-
dized to the active 5-hydroxymethyl tolterodine by CYP2D6
and N-dealkylated by CYP3A4, 2C9 and 2C19 (see supple-
mentary figure 40, Supplemental Digital Content 1).[276-278]
Studies have reported that 5-hydroxymethyltolterodine was
the major metabolite in EMs but undetectable in the plasma of
PMs.[279-282] Although tolterodine concentrations have been
shown to be increased 5- to 10-fold in PMs, the summed active
moieties did not differ between EMs and PMs.[280-283] This
suggests that therapeutic effects would not differ significantly
between the two groups, and there is no convincing evidence of
an important gene-effect correlation.[279]
Based on the above findings, the CYP2D6 phenotype can be
used to predict the hydroxylation activity of tolterodine. There
is a possibility of clinical drug interaction when tolterodine is
coadministered with a CYP2D6 inhibitor or to individuals as-
sociated with the CYP2D6 PM phenotype. However, the large
amount of CYP3A in the liver and the fact that tolterodine is
predominantly eliminated via oxidation by CYP2D6 make it
less likely that clinically significant drug-drug interactions
would occur with CYP3A substrates in individuals with the
CYP2D6 EM phenotype.
1.7 Antiemetics
Tropisetron, ondansetron, palonosetron, granisetron and
dolasetron are 5-HT3 receptor antagonists used in the control
of chemotherapy-induced nausea and vomiting.[284-287] They
are also used in prophylaxis and treatment of postoperative
nausea and vomiting. Ezlopitant and aprepitant are both
nonpeptidic antagonists of neurokinin-1 receptors and are used
as antiemetics.[288] Metoclopramide is mainly used as a gas-
troprokinetic and antiemetic agent. CYP2D6 is involved in the
metabolism of several antiemetics to some extent, including
tropisetron,[289,290] ondansetron,[291,292] palonosetron, dolase-
tron,[292] ezlopitant[293] and metoclopramide.[294]
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5-HT3 receptor antagonists have the same mechanism of
action but have different chemical structures and receptor
binding affinity.[295] Granisetron, dolasetron and its major
metabolite are selective 5-HT3 receptor antagonists, while on-
dansetron and tropisetron are weak antagonists for 5-HT4 re-
ceptors. Ondansetron has also been demonstrated to bind at
other serotonin receptors and to the m opioid receptor. The half-lives of granisetron, tropisetron and the active metabolite of
dolasetron are 2–3 times longer than that of ondansetron.[295]
Tropisetron hydroxylation is primarily by CYP2D6, whereas
that of ondansetron is dependent on CYP2D6 and 2E1.[292]
Ezolopitant is metabolized by both CYP2D6 and 3A4,[296]
whereas aprepitant is mainly metabolized by CYP3A4.[297]
Metoclopramide is largely metabolized by CYP2D6 to mono-
deethylmetoclopramide via N-dealkylation,[294] while granise-
tron is almost entirely metabolized by CYP3A4.
1.7.1 Dolasetron
Dolasetron is a pseudopelletierine-derived 5-HT3 receptor
antagonist used for the treatment of chemotherapy-, radio-
therapy- and surgery-induced emesis.[298] Dolasetron is rapidly
metabolized (t½ <1 hour) by carbonyl reductase, with subsequent
formation of an active metabolite, hydrodolasetron (reduced
dolasetron), which is further metabolized by CYP2D6 and 3A4
(plasma t½ 7–8 hours) [see supplementary figure 41, Supple-
mental Digital Content 1].[292] Reduced dolasetron undergoes
oxidation of the indole aromatic ring at positions 5, 6 and 7, and
also N-oxidation. Reduced dolasetron accounts for 17–54% of
the dose in urine, and hydroxylated metabolites of reduced
dolasetron have been shown to represent up to 9% of the dose in
urine.[299] The hydroxylation of reduced dolasetron is mediated
by CYP2D6, and its N-oxidation is catalysed by CYP3A4.[292]
In a clinical trial of 150 patients comprising eight PMs,
four IMs, 128 EMs and ten UMs, there were no statistically
significant differences in the incidence of nausea and vomiting
in PMs, IMs and EMs treated with dolasetron or granise-
tron.[300] However, UMs with duplication of the CYP2D6
allele (n = 10) experienced significantly more vomiting epi-
sodes than patients in the granisetron group during the
24-hour observation period.[300] However, this study did
not measure the plasma concentrations of dolasetron and
hydrodolasetron.
1.7.2 Ondansetron
Ondansetron is a potent and selective 5-HT3 receptor an-
tagonist used mainly as an antiemetic to treat and prevent
nausea and vomiting induced by chemotherapy and radio-
therapy and postoperative nausea and vomiting.[295,301] On-
dansetron is extensively metabolized in humans, with ~5% of a
radiolabelled dose being recovered as the parent drug from the
urine. The primary metabolic pathway is hydroxylation on the
indole ring in the 6, 7 and 8 positions by CYP2D6, 3A4
and 1A2, followed by glucuronide or sulphate conjugation
(see supplementary figure 42, Supplemental Digital Content
1).[291,292] In terms of overall ondansetron elimination,
CYP3A4 plays the predominant role. Because of the multi-
plicity of metabolic enzymes capable of metabolizing ondan-
setron, it is likely that inhibition or loss of one enzyme (e.g.
CYP2D6 deficiency) will be compensated for by others and
may result in little change in overall rates of ondansetron
elimination. In healthy subjects, there was no difference in the
AUC, Cmax and t½ of ondansetron between EMs (n = 6) and
PMs (n = 6) receiving a single dose (8mg intravenously).[302]
In a study of 250 patients undergoing standardized general
anaesthesia who were given ondansetron 4mg 30 minutes be-
fore extubation, UMs (n = 23) had increased therapeutic failure
and a reduced response to ondansetron.[303] Postoperative vo-
miting was significantly higher in UMs (46%) than in EMs
(15%), IMs (17%) and PMs (8%). In patients with one, two or
three functional CYP2D6 copies, the incidences of vomiting
were 27%, 14% and 30%, respectively. There were no differ-
ences between groups in the incidence of nausea based on the
CYP2D6 copy number or genotype. However, the plasma
concentration of ondansetron was not determined in this study,
although it could be expected that UMs metabolize ondanse-
tron faster via CYP2D6 than other genotype groups. These
results indicate that patients with three copies of the CYP2D6
gene, a genotype consistent with the UM phenotype, show an
increased incidence of ondansetron failure for the prevention of
postoperative vomiting but not nausea.
1.7.3 Tropisetron
Tropisetron is a highly potent and selective 5-HT3 receptor
antagonist used as an antiemetic in cancer chemother-
apy.[304,305] It is extensively metabolized by hydroxylation of
the indole ring in the 5, 6 and 7 positions, followed by con-
jugation in humans (see supplementary figure 43, Supplemental
Digital Content 1).[289,290] The major route of elimination of
tropisetron in EMs is via metabolism to 6-hydroxytropisetron
and 5-hydroxytropisetron and their conjugates (~50–60% of the
dose excreted), whereas PMs excrete only trace amounts.[306]
In one study, CYP2D6 catalysed 5- and 6-hydroxylation of tro-
pisetron, while CYP3A4 formed N-desmethyltropisetron.[306]
PMs had 5- to 7-fold higher AUC values for tropisetron than
EMs. A Korean study (n = 13) reported a 6.8-fold higher mean
AUC in subjects with the CYP2D6*10/*10 and *5/*10 geno-
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types compared with the wild-type and a 1.9-fold higher AUC
in those with theCYP2D6*1/*10 genotype.[307] No difference in
adverse effects was seen, consistent with the high therapeutic
index of this drug.
Data from a small number of UMs suggest that they have
similar or slightly reduced concentrations compared with
EMs,[307,308] with a decreased antiemetic effect shown in one
study.[308] In the later study of healthy subjects, carriers of the
duplicated CYP2D6 allele showed a decrease in the AUC, Cmax
and t½ for tropisetron comparedwithwild-type allele carriers.[308]
1.7.4 Summary of Antiemetics
Dolasetron, ondansetron and tropisetron, all in part meta-
bolized by CYP2D6, are less effective in UM patients than in
other subjects. Overall, there is a strong gene-concentration
relationship for tropisetron only. CYP2D6 genotype screening
prior to antiemetic treatment may allow for modification of
antiemetic dosing. An alternative is to use a 5-HT3 receptor
antagonist that is metabolized independently of CYP2D6, such
as granisetron, which would obviate the need for genotyping
and may lead to an improved drug response.
1.8 Antihistamines
Antihistamines are used in the treatment of allergies. First-
generation H1 receptor antagonists such as diphenhydramine,
chlorpheniramine (chlorphenamine), triprolidine and hydro-
xyzine frequently cause somnolence or otherCNSadverse effects.
Second-generation antihistamines such as terfenadine, astemi-
zole, loratadine and cetirizine, being more lipophobic, offer the
advantages of a lack of CNS and cholinergic effects such as se-
dation and dry mouth.[309] However, terfenadine and astemizole
have been withdrawn from the market, since both have
shown rare but lethal cardiotoxic adverse effects (e.g. QT interval
prolongation). Third-generation antihistamines, which are me-
tabolites of the earlier drugs (e.g. fexofenadine, levocetirizine and
desloratadine), have been shown not to have the cardiac effects of
their parent drugs and are at least as potent.[310] CYP2D6 is a
major contributor to the oxidation of several antihistamines,
including loratadine,[311,312] promethazine,[313] astemizole,[314] me-
quitazine,[315] terfenadine,[316] azelastine,[317,318] oxatomide,[319,320]
epinastine,[321] cinnarizine,[322,323] flunarizine,[322,323] diphenhy-
dramine[324] and chlorpheniramine.[325,326]
1.8.1 Chlorpheniramine (Chlorphenamine)
Chlorpheniramine is a first-generation alkylamine H1 re-
ceptor antagonist, which is available as an over-the-counter
drug for treatment of the common cold and for symptomatic
treatment of allergic conditions such as rhinitis and urticar-
ia.[309] Chlorpheniramine has a chiral carbon and is usually
given as a racemic mixture, and it demonstrates stereo-
selectivity in its disposition and pharmacological response.[327]
The S-enantiomer is ~100 times more potent in antihistamine
activity than the R-enantiomer. In humans, chlorpheniramine
is N-demethylated by CYP2D6 (see supplementary figure 44,
Supplemental Digital Content 1). Five metabolites of chlor-
pheniramine have been detected in urine or in plasma after
dosing of chlorpheniramine in humans, includingN-desmethyl-
and didesmethyl-chlorpheniramine, and several unidentified
polar metabolites as well.[328]
In healthy EM subjects (n= 6), the mean Cmax of chlorphe-
niramine was greater (12.55 vs 5.38 ng/mL) and its oral clearance
was lower (0.49 vs 1.07L/h/kg) for the S-enantiomer than for
R-chlorpheniramine, following a single oral 8mg dose.[326] For
S-chlorpheniramine, low-dose quinidine (a potent inhibitor of
CYP2D6) caused a slight increase in the Cmax to 13.94ng/mL, a
marked decrease in oral clearance to 0.22L/h/kg), and a pro-
longation of the t½ from 18.0 to 29.3 hours. Quinidine also de-
creased oral clearance of R-chlorpheniramine to 0.60L/h/kg. InPMs (n= 2), systemic exposure was greater after administration
of chlorpheniramine than in EMs, and coadministration of qui-
nidine caused only a slight increase in oral clearance and a small
decrease in the AUC of both R- and S-chlorpheniramine.[326]
These findings demonstrate stereoselective elimination of chlor-
pheniramine in humans, with the most pharmacologically active
S-enantiomer being cleared more slowly than the R-enantiomer.
Low dosages of quinidine effectively convert the EM phenotype
to the PM phenotype, indicating a role of CYP2D6 in the me-
tabolic clearance of chlorpheniramine.
In addition, a marked difference in H1 receptor occupancy
has been observed between healthy PMs (n = 5) and EMs (n = 6)
after a single 8mg dose of chlorpheniramine.[329] In EMs, there
was >80% occupancy ofH1 receptors by antagonists in the plas-
ma for 12 hours postdose, but the occupancy was >60% from 12
to 30 hours in PMs, when plasma concentrations had decreased
to the level that produced 50% occupancy of receptors. These
findings suggest that plasma concentrations of chlorphenir-
amine cannot predict the extent of H1 receptor occupancy, and
CYP2D6 appears to form a potent active metabolite from
chlorpheniramine. The CYP2D6 phenotype should have a
minimal impact on the clinical effect of chlorpheniramine.
1.8.2 Diphenhydramine
Diphenhydramine is a member of the ethanolamine class of
first-generation antihistamine agents and is also antiemetic,
sedative and hypnotic.[330] It may also be used for the treatment
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of extrapyramidal adverse effects of typical antipsychotics,
such as the tremors caused by haloperidol.[331] Diphenhy-
dramine is extensively metabolized by N-demethylation to
N-desmethyl diphenhydramine, followed by rapid demethylation
to N,N-didesmethyl diphenhydramine, which is further metabo-
lized by oxidative deamination to diphenylmethoxyacetic acid
(see supplementary figure 45, Supplemental Digital Content
1).[332,333] These metabolic pathways are thought to be major
pathways in humans. CYP1A2, 2C9 and 2C19 are low-affinity
components for theN-demethylation of diphenhydramine, while
CYP2D6 catalyses this reaction as the high-affinity enzyme.[324]
In addition, CYP2C18 and 2B6 also play a role at a relatively
higher substrate concentration (‡20mmol/L).[334]Diphenhydramine
also undergoes direct glucuronidation at its tertiary amino group,
with formation of a quaternary ammonium glucuronide.[335-337]
Lessard et al.[338] reported that the clearance of diphenhy-
dramine to its N-demethylated metabolite, 2-benzhydryloxy-
N-methyl-ethanamine, is similar inEMs andPMsof substrates of
CYP2D6, suggesting a limited role ofCYP2D6 in themetabolism
of diphenhydramine. There is no need to conduct CYP2D6
genotyping/phenotyping tests for patients taking diphenhy-
dramine.
1.8.3 Loratadine
Loratadine is an orally effective, nonsedating, long-acting
tricyclic H1 receptor antagonist indicated for the treatment of
allergic rhinitis and urticaria.[339] It undergoes extensive meta-
bolism (60–70%) mainly by CYP3A4 and, to a lesser extent, by
CYP2D6 to its major active metabolite desloratadine (i.e.
descarboethoxyloratadine) [see supplementary figure 46, Sup-
plemental Digital Content 1].[311] However, the catalytic for-
mation rate was ~5-fold greater in recombinant CYP2D6 than
in CYP3A4. Desloratadine is detected in the plasma at low
concentrations and is converted to several hydroxylated me-
tabolites, including the activemetabolites, 3-OH-desloratadine,
5-OH- and 6-OH-desloratadine, which are excreted as glucur-
onides.[312,340] In humans, the major circulating metabolites of
loratadine include 3-OH-desloratadine glucuronide and dihy-
droxy-desloratadine glucuronides.[341]
Following a single 20mg dose, the oral clearance rates of
loratadine in healthy Chinese subjects who were homozygous
for the nonfunctional CYP2D6*10 allele (n = 7), heterozygous
for CYP2D6*10 (n = 6) or homozygous for CYP2D6*1 (wild-
type; n= 4) were 7.17, 11.06 and 14.59 L/h/kg, respectively.[342]
The corresponding MR values of the AUCs of desloratadine
over those of loratadine were 1.55, 2.47 and 3.32. In homo-
zygousCYP2D6*10 carriers, the AUC of loratadine was 75.5%and 123.6% higher than in heterozygous CYP2D6*10 and
homozygousCYP2D6*1 subjects, respectively. However, there
was no significant difference in the plasma concentrations of
desloratadine between the three genotype groups, although
there was a trend for increased desloratadine concentrations in
subjects with one or two CYP2D6*10 alleles. These results in-
dicate a clear gene-dose effect on loratadine in Chinese, but the
impact ofCYP2D6 polymorphisms on the efficacy and adverse
effects of loratadine is yet to be determined.
1.8.4 Summary of Antihistamines
There are limited data on the association of CYP2D6 poly-
morphisms and the pharmacokinetics and pharmacodynamics of
antihistamines. The preliminary data indicate a gene-dose effect
on chlorpheniramine and loratadine, but not on diphenhy-
dramine. It appears that theCYP2D6 genotype is associated with
the adverse effects of antihistamines. A recent study in Japanese
patients has reported that patients with the nonfunctional
CYP2D6*10 allele experienced more hypersomnia than those
carrying the wild-type gene.[343] Since antihistamines have rela-
tively wide therapeutic ranges, there is no need to adjust their
dosage based on the CYP2D6 phenotype.
1.9 Opioids
Opioids have long been used as potent analgesics. They bind
to specific opioid receptors (m, k and d) in the CNS and in other
tissues, and produce different pharmacological responses de-
pending on which receptor they bind to, the affinity for that
receptor, and whether the opioid is an agonist or an antagonist.
Almost all opioids are subject to O-dealkylation, N-deal-
kylation, ketoreduction or deacetylation, leading to oxidative
metabolites.[344] Through glucuronidation or sulphation, phase
II metabolites are generated. Some metabolites of opioids are
pharmacologically active and contribute to the effects of the
parent compound. CYP2D6 is involved in the oxidative me-
tabolism of several opioids, including dextromethorphan, tra-
madol, codeine, dihydrocodeine, hydrocodone and oxycodone.
1.9.1 Codeine
Codeine is used to treat moderate to mild pain and is ex-
tensively used as a cough suppressant. Codeine itself is a weak mopioid receptor agonist. Approximately 10% of an oral codeine
dose (30–60mg) is metabolized by CYP2D6-mediated O-de-
methylation into its active form, morphine,[345] which is the key
metabolite responsible for the most antinociceptive effect of
codeine. The majority of a codeine dose is glucuronidated to
codeine-6-glucuronide, and the remainder is metabolized by
CYP3A4 to norcodeine (see supplementary figure 47, Supple-
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mental Digital Content 1).[346] Morphine is converted to its
3-O- and 6-O-glucuronide by UGT1A1, 1A8 and 2B7.[347]
Morphine isN-demethylated to result in normorphine, which is
then glucuronidated.
The analgesic effect of codeine has been reported to be
substantially lesser in subjects found to be PMs,[348] and other
studies have reported no analgesic effect in PMs.[349,350] The
AUC of codeine is similar in PMs and EMs, whereas morphine
is virtually undetectable in PMs.[349,351] Clearly, a lack of the
CYP2D6 enzymewould be expected to result in reduced plasma
morphine concentrations and thus reduce the effectiveness of
the drug. Ironically, subjects who are deficient in CYP2D6
metabolism are protected against possible opioid dependence,
as none of the PM subjects in the study populations showed
symptoms or signs of dependence.[352-354] However, further
research is required to establish the validity of such findings.
TheCYP2D6 genotype may be used to predict possible adverse
effects associated with codeine treatment and the likelihood of
their occurrence, especially in PMs.[355]
Recently, a fatal case of a neonate was reported by Koren
et al.,[356] in which death was caused by high concentrations of
morphine resulting from high doses of codeine taken by a
breastfeeding mother who was a UM. A case-control study
found that infants fed by mothers who were EMs experienced
more CNS depression than those fed by PM mothers, and two
breastfeeding mothers whose infants exhibited severe neonatal
toxicity (i.e. CNS depression) were UMs.[357] It is clear that the
UM phenotype of the mother resulted in excessive morphine
from codeine, which was then excreted into the milk taken by
the infants, who then experienced CNS depression or even died.
Therefore, breastfeeding mothers should be advised not to take
codeine as an analgesic; alternative drugs that are not CYP2D6
substrates should be chosen.
1.9.2 Dihydrocodeine
Dihydrocodeine is a semisynthetic opioid analogue used as an
analgesic andantitussive.[358] Similarly to codeine, dihydrocodeine
is converted byCYP2D6 to dihydromorphine (see supplementary
figure 48, Supplemental Digital Content 1), which has activity
comparable to that of morphine.[359] Dihydrocodeine is mostly
glucuronidated to form dihydrocodeine-6-glucuronide or is N-
demethylated by CYP3A4 to nordihydrocodeine. Dihydromor-
phine is converted to its 3-O- and 6-O-glucuronides or sulphates.
EMs have 7-fold higher dihydromorphine concentra-
tions,[360] with quinidine producing a 3- to 4-fold decrease in
dihydromorphine concentrations.[361] Contrary to what might
be expected, dihydrocodeine 60mg has been reported to pro-
duce similar analgesic effects in healthy subjects who were EMs
or PMs.[361,362] However, in one of the studies, no analgesic
effect of dihydrocodeine was seen in the pain thresholdmodel in
either EMs or PMs, whereas pupillary diameter was reduced
comparably in both EMs and PMs.[362]
1.9.3 Hydrocodone
Hydrocodone is a semisynthetic opioid analogue used to treat
moderate pain and as an antitussive. Hydrocodone differs
structurally from codeine in that the C6 position is occupied by a
keto group, and thus it does not undergo the extensive conjuga-
tion (>60%) that codeine undergoes. The therapeutic range of
hydrocodone is 1–30ng/mL, and the toxic plasma concentration
is>100ng/mL.About 26%of a single dose is excreted in a 72-hour
urine collection, which consists of unchanged drug (~12%), nor-
hydrocodone (5%), conjugated hydrocodone (4%), 6-hydrocodol
(3%) and conjugated 6-hydromorphol (0.1%). About 40% of the
clearance of hydrocodone is via non-CYP pathways. The meta-
bolism of hydrocodone is similar to that of codeine, resulting in
the major active metabolite hydromorphone (see supplementary
figure 49, Supplemental Digital Content 1). The m opioid re-
ceptor-binding affinity of hydromorphone is 10- to 33-fold
greater than that of hydrocodone.[363] Hydrocodone is metabo-
lized by O- and N-demethylation, resulting in hydromorphone
and norhydrocodone, respectively, and reduction of the 6-keto
group.C6-keto reduction results in approximately equal amounts
of 6-a-hydrocol and 6-b-hydrocol. The O-demethylation of hy-
drocodone is predominantly catalysed by CYP2D6 and, to a
lesser extent, by an unknown low-affinity CYP.[364] Norhy-
drocodone formation has been shown to be mediated by
CYP3A4. Liver microsomes from the livers of PMs formed
substantially less hydromorphone than did the microsomes from
the EM liver (0.7 vs 3.5 mL/h/mg protein), but the CYP2D6
genotype did not affect norhydrocodone formation.[364]
The urinary MR of hydrocodone/hydromorphone was cor-
related with the O-demethylation ratio for dextromethorphan
in healthy subjects.[365] The production of hydromorphone was
significantly decreased in PMs compared with EMs.[365] The
relative contribution of norhydrocodonewas increased, with an
increase in the amount of hydrocodone recovered unchanged in
the urine of PMs (18% vs 10%). The partial clearance of hy-
drocodone to hydromorphone in PMs was 8-fold lower than in
EMs (3.4 vs 28.1mL/h/kg.[365] Pretreatment with quinidine
100mg decreased the partial clearance to levels similar to those
seen in PMs (5.0 – 3.6mL/h/kg), and the Cmax of hydro-
morphone was 5-fold higher in EMs than in PMs or in EMs
pretreated with quinidine.[365] Lelas et al.[366] reported that in-
hibition of hydromorphone formation by quinidine resulted in
plasma hydromorphone concentrations that were approxi-
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mately 10% of those of controls in rhesus monkeys but resulted
in negligible effects on the antinociceptive actions of hydro-
codone. However, there is little evidence for a marked differ-
ence in analgesic and adverse effects between EMs and PMs in
human studies,[365,367] although more positive opioid effects
were seen in EMs than in PMs over the first hour postdose.[365]
1.9.4 Oxycodone
Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is a semi-
synthetic opioid analogue used in the treatment of moderate to
severe postoperative pain and pain associated with cancer.[368]
Oral oxymorphone is 10-fold more potent than oral morphine
based on the dose. Oxycodone is extensively metabolized; only
10% of a dose is excreted unchanged in the urine.[369] Its me-
tabolism is similar to that of codeine and hydrocodone, with
O- andN-demethylation being the major pathways, resulting in
oxymorphone and noroxycodone, respectively (see supple-
mentary figure 50, Supplemental Digital Content 1). Oxymor-
phone is a potent opioid that has a 3- to 5-fold higher m opioid
receptor affinity than that of morphine.[363] Noroxycodone also
has binding activity. CYP3A4 and 3A5 displayed the highest
activity for oxycodone N-demethylation (>90%), whereas
CYP2D6 showed the highest activity for O-demethylation.[370]
The total CLint for noroxycodone formation was 8-fold greater
than that for oxymorphone formation in human liver micro-
somes. Experiments with human intestinal mucosal micro-
somes indicated lower N-demethylation activity (20–50%)
compared with liver microsomes and negligible O-demethyla-
tion activity, indicating a minor contribution of intestinal mu-
cosa in the first-pass oxidative metabolism of oxycodone.[370]
CYP2D6 is the principal (70–90%)O-demethylase of oxyco-
done, and oxymorphone formation in human liver microsomes
has been reported to be much lower in PMs than in EMs, and
was inhibitedbyquinidine.[371]However, inhibitionofCYP2D6by
quinidine did not attenuate the opioid-induced psychomotor
and subjective adverse effects of oxycodone in human sub-
jects,[372] although no oxymorphone was detected in the plasma
of eight of ten subjects.[372] However, analgesia was not assessed
because pain was not present. A significant reduction in plasma
oxymorphone concentrations does not substantially alter the
pharmacodynamic effects of oxycodone. There is little evidence
of a difference in the opioid effect between EMs and PMs in
human studies.[372] It appears that oxymorphone plays a minor
role in the pharmacodynamics of oxycodone.
1.9.5 Methadone
Methadone is a synthetic opioid analogue acting as a m opioid
receptor antagonist and is widely used for the treatment of opioid
dependence and chronic pain.[373] The clinically used methadone
is a mixture of R- and S-enantiomers, with R-methadone being
the major pharmacologically active form. The affinity of R-
methadone for m and d opioid receptors and its analgesic activity
are 10- and 50-fold higher, respectively, than those of theS-enanti-
omer.[374] Methadone shows considerable interindividual
variability in its pharmacokinetics and pharmacodynamics.[375]
In humans, methadone is extensively metabolized, and one major
metabolic pathway is N-demethylation mainly by CYP3A4
and, to a lesser extent, by 2D6 to 2-ethylidene-1,5-dimethyl-3,
3-diphenylpyrolidine, with contributions from CYP2B6, 2C8
and 2C19 (see supplementary figure 51, Supplemental Digital
Content 1).[376]
In 56 Caucasian patients on methadone maintenance treat-
ment, the oral clearances ofR-, S- and racemicmethadone varied
5.4-, 6.8- and 6.1-fold, respectively.[377] There was no significant
difference in methadone oral clearance between PMs, IMs and
EMs. In another study of 245 patients receiving methadone
maintenance treatment, UMs had lower trough methadone
plasma concentrations than EMs plus IMs (2.4 vs 3.3 ng/mL/mg
dose), but the PM phenotype did not affect the plasma con-
centrations of methadone.[378] It appears that methadone inhibits
CYP2D6, since a study in 34 Caucasian patients undergoing
methadone maintenance treatment revealed a discordance be-
tween the CYP2D6 genotype and the phenotype.[379]While 9% of
patients (3/34) were PMs carrying nonfunctional *4/*4, 57%(16/28) were PMs according to phenotyping tests. Eight patients,
who were genotypically EMs carrying the functionalCYP2D6*1allele, were classified as PMs by their phenotype, using dex-
tromethorphan as a probe. The high proportion of phenotypic
PMs in patients onmethadonemaintenance therapy is consistent
with significant inhibition of CYP2D6 activity by methadone
seen in vitro.[380] Because CYP2D6 is involved in the metabolism
of a number of clinically important drugs, the observed decrease
in CYP2D6 activity during methadone treatment may affect the
efficacy and toxicity of these drugs. Clinicians should be aware of
the potential for CYP2D6-mediated drug interactions in EM
patients on long-term methadone therapy.
In a study of addict patients (n = 14), the mean increase in the
R-methadone concentration/dose ratio with coadministered
quetiapine was 7%, 21% and 30%, respectively, in PMs, het-
erozygous EMs and homozygous EMs.[237] In healthy subjects,
paroxetine (a potent CYP2D6 inhibitor) significantly increases
the plasma concentrations ofR- andS-methadone.[99,381] In addi-
tion, in twoPMs, only the plasma concentration ofS-methadone,
but not that of R-methadone, was increased by coadministered
paroxetine.[381] Fluoxetine, another potent inhibitor of CYP2D6,
has been found to stereoselectively increase the concentration of
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R- but not that of S-methadone.[382] However, fluvoxamine
nonselectively increased the plasma concentrations of both
R- and S-methadone.[382] One study found that fluconazole
increased the plasma peak and trough concentrations of
methadone by 27% and 48%, respectively, in healthy subjects
(n= 13).[383]
These findings suggest that CYP2D6 plays only a minor to
moderate role in the metabolism of methadone, while CYP3A4
and 2B6 may play a more important role. The disposition and
clearance of methadone is thus not significantly affected by the
CYP2D6 polymorphism. The R-enantiomer is preferentially
metabolized by CYP2D6 and the S-enantiomer by CYP1A2.
The CYP2D6 phenotype has a moderate effect on drug inter-
action with methadone.
1.9.6 Tramadol
Tramadol is a synthetic opioid analgesic used for the treat-
ment of moderate to severe pain.[384] Tramadol is marketed as a
racemic mixture with a weak affinity for the m opioid receptor.
The (+)-enantiomer is ~4-fold more potent than the (-)-en-antiomer in terms of m opioid-receptor affinity and serotonin
reuptake, whereas the (-)-enantiomer is largely responsible for
the norepinephrine reuptake effect.[384] These activities appear
to result in a synergistic analgesic effect, with (+)-tramadol
showing 10-fold higher analgesic activity than (-)-trama-
dol.[384] Tramadol is mainly metabolized by O- and N-de-
methylation and phase II conjugation. TheO-demethylation of
tramadol to active O-desmethyl-tramadol (M1) is catalysed by
CYP2D6, whereas N-demethylation to N-desmethyltramadol
(M2) is catalysed by CYP2B6 and 3A4 (see supplementary
figure 4, Supplemental Digital Content 1).[385,386] M1 has a 200-
fold higher affinity for m opioid receptors than the parent drug.
A relationship has been found between tramadolO-demethy-
lation and sparteine oxidation in human subjects (n= 71).[385] The
meanMR of tramadolO-demethylation was significantly higher
in PMs than inEMs (4.4 vs 0.8). Another study in 26 children also
reported a close correlation between tramadol/O-desmethyl-
tramadol plasma concentrations or AUCs and dextromethor-
phan MRs.[387] The plasma concentrations of the pharmacolo-
gically active O-desmethyltramadol (M1) were markedly higher
(10–100ng/mL) in EMs than in PMs, who had concentrations
below or around the detection limit of 3.0 ng/mL after an oral
dose of tramadol at 2mg/kg bodyweight.[388] Analgesia for ex-
perimental pain is present in both EMs and PMs but much
weaker in PMs owing to less formation of M1, which acts on the
opioid component. Tramadol 100mg injected intravenously has
been shown to decrease discomfort experienced during the cold
pressor test in EMs.[389] The pain tolerance thresholds to sural
nerve stimulation were increased in PMs, whose plasma con-
centrations of M1 were lower (below the limit of detection,
~5.1 ng/mL) than those in EMs (12–17ng/mL).[389] These results
indicate that M1 plays a major role in the analgesic effect of
tramadol, but tramadol also shows some analgesic activity.
In healthy subjects (n= 21) receiving a single 100mg dose of
tramadol in a slow-release formulation, the Cmax of tramadol in
PMs (n= 7) was 21.7% and 40.9% higher than those in hetero-
zygous and homozygous EMs (n= 7 for each phenotype),
respectively.[390] The AUC of tramadol in PMs was 35.8% and
56.8% higher than in heterozygous and homozygous EMs, re-
spectively. Consistent with this, the t½ in PMs was 64.3% and
75.6% longer than in heterozygous and homozygous EMs,
respectively (25.89 vs 9.23 vs 6.31 hours). As expected, the for-
mation ofM1 and subsequently the plasma concentrations of this
active metabolite were significantly decreased in PMs, with the
Cmax being ~3.9-fold lower than in both homozygous and het-
erozygous EMs (41 vs 158 vs 151nmol/mL).[390] The ratios of the
tramadol AUCs to those of M1 were 16.8, 2.98 and 2.23 in PMs,
heterozygous EMs and homozygous EMs, respectively. In ad-
dition, PMshad almost 2.2- and 3.2-fold lowermaximal pupillary
constriction at 4 hours postdose than heterozygous and homo-
zygousEMs, respectively (0.58 vs 1.25 vs 1.83mm).[390] Therewas
a significant correlation between theAUCandCmax values ofM1
and pupillary constriction.
Fliegert et al.[391] investigated the effect of CYP2D6 status on
the pharmacokinetics of tramadol and static and dynamic pu-
pillometry in healthy subjects (n= 26) receiving a single dose of
tramadol 50–150mg. PMs (n= 6) exhibited 1.5- to 1.7-fold higher
plasma concentrations and AUC values of both enantiomers of
tramadol than EMs (n= 20), and the concentrations of M1 were
1.5-fold lower [for (-)-M1] than those seen in EMs or below the
lower limit of quantification [for (+)-M1]. PMs had 1.3- to 1.5-
fold longer t½ values for tramadol and M1. In PMs, both max-
imum effects and the return to baseline occurred much earlier (at
~3 and 8 hours, respectively) than in EMs, where the effects of
tramadol on static and dynamic pupillometry slowly reached a
maximum between 4 and 10 hours postdose and decreased until
24 hours.[391] However, the effect-time profiles, amplitude of
change, velocity of constriction and reaction duration, as well as
an increase in latency, were comparable in PMs and EMs. The
pharmacokinetic properties of tramadol in PMs and EMs may
provide an explanation for most of the pupillometry findings
from this study. The pupillometric response appears to be mainly
mediated by (+)-M1 in EMs, which binds to m opioid receptors,
whereas the non m opioid receptor component [e.g. the parent
enantiomers and (-)-M1] seems to play an important role in PMs.
Indeed, the analgesic effects of tramadol are attenuated but not
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abolished in PMs. The lack of initial miosis in PMs clearly can be
attributed to the lack of formation of (+)-M1. Although the
maximumplasma concentrations of (+)-M1 did not coincidewith
the maximum pupillometric effects, a delayed appearance of the
enantiomers of tramadol andM1 in the CNS due to the action of
the blood-brain barrier may explain this delay.
A study in Chinese gastric cancer patients (n = 63) recovering
from major abdominal surgery reported that the total con-
sumption of tramadol over 48 hours in individuals carrying the
nonfunctional CYP2D6*10/*10 allele (n = 20) or one *10 allele
(n = 26) was significantly higher than that in individuals of the
wild-type (n = 17) [532.7 vs 476.8 vs 459.5mg at 24 hours
postoperation].[392] Healthy subjects harbouring at least one
CYP2D6*10 allele had significantly longer t½ of tramadol after
a single dose than subjects carrying the wild-type gene.[389,393] A
recent study in 88 Faroese patients reported a ~14-fold higher
M1/tramadol ratio in EMs (n = 78) than in PMs (n = 10).[394] In
Malaysian patients, the UMs and EMs had 2.6- and 1.3-fold
greater clearance of tramadol, respectively, than IMs carrying
the CYP2D6*10 allele.[395] The clearance values of tramadol
were 16, 18, 23 and 42L/h, and themean t½ values were 7.1, 6.8,
5.6 and 3.8 hours in IMs, heterozygous EMs, homozygous EMs
and UMs, respectively.[395] It was found in this study that there
were significant differences in the adverse effects among the
various genotype groups, with IMs experiencing more adverse
effects than EMs, and EMs having more adverse effects than
UMs.[395] Adverse effects may be greater in EMs, through
greater opioid effects mediated by M1.[388,389,395]
Significantly higher tramadol AUC values and lower AUC
values of M1 were observed in Caucasian subjects after single
oral, multiple oral and intravenous administration of trama-
dol.[396,397] In Spanish healthy subjects (n= 24), the plasma con-
centrations of (+)- and (-)-tramadol enantiomers were higher in
PMs (n= 5) than in EMs (n= 19), with 1.98- and 1.74-fold dif-
ferences in theAUC, respectively.[398] The oral clearance values of
(+)- and (-)-tramadol were 1.91- and 1.71-fold greater in PMs,
which was related to difference in both O- and N-demethylation
in PMs and EMs. The mean AUC values for (+)- and (-)-O-
desmethyltramadol (M1) were 4.33- and 0.89-fold greater in EMs
than in PMs, and the values for (+)- and (-)-N-desmethyl-
tramadol (M2) were 7.40- and 8.69-fold greater in PMs than
those in EMs, because of to the involvement of CYP2D6 in their
subsequent oxidation.[398] In EMs, the plasma concentrations of
endogenous epinephrine increased after tramadol administra-
tion,whereas no effect was observed in PMs. These results further
support the major contribution of CYP2D6 in the formation
of M1 from tramadol, and the N-desmethylation pathway was
indirectly affected by CYP2D6 phenotype.
PMs appeared to show a lower response rate to postoperative
tramadol administration than EMs.[399] However, evidence is
weak on the impact of CYP2D6 polymorphisms on the analgesic
effect of tramadol. There are case reports indicating that carriers
of theCYP2D6 duplication with the UM phenotype treated with
opioids may be at high risk of adverse events.[400,401] The Cmax of
(+)-O-desmethyltramadol (M1) after a single dose of tramadol
100mg was found to be significantly higher in UMs (n= 11) than
in EMs (n= 11), with median AUCs of 448 and 416mg � h/L,respectively.[402] ThemedianAUCs of (+)-tramadol were 786 and
587mg � h/L in EMs and UMs. There was an increased pain
threshold and pain tolerance in the cold pressor test and stronger
miosis after tramadol dosing in UMs than in EMs. Almost 50%of UMs experienced nausea compared with only 9% of EMs.
These results suggest that tramadol may frequently cause adverse
effects in southernEuropeans andNorthernAfricans,with a high
proportion of CYP2D6 duplication and the UM phenotype.
The pharmacodynamic profiling of tramadol is very com-
plex, and the relative contribution of tramadol and its meta-
bolites is unknown. There is a clear gene-dose effect on
tramadol and M1 formation. However, since tramadol can
exert a non m opioid receptor mechanism of action that relates
to inhibition of reuptake of norepinephrine and serotonin, we
would expect an excess of nonopioid mechanisms of action in
PMs as compared with EMs.
1.9.7 Summary of Opioids
Polymorphic CYP2D6 catalyses the O-demethylation
pathway ofmany 4,5-epoxymorphinan opioids such as codeine,
oxycodone, hydrocodone and dihydrocodeine, while their N-
demethylation is mediated principally by CYP3A4. CYP2D6
inhibition studies with hydrocodone, dihydrocodeine or oxy-
codone have all failed to demonstrate any significant effect on
subjective opioid responses in human subjects, suggesting a
minor role of the active metabolites formed by CYP2D6-
mediatedO-demethylation. There is a clear gene-dose effect on
the formation O-demethylated metabolites, but the clinical
significance may be minimal, as the analgesic effect is not al-
tered in PMs. Genetically caused inactivity of CYP2D6 renders
codeine ineffective owing to lack of morphine formation, de-
creases the efficacy of tramadol owing to reduced formation of
the active O-desmethyl-tramadol and reduces the clearance of
methadone. CYP2D6 polymorphisms may also trigger or modify
drug interactions, which in turn can alter the clinical response
to opioid therapy.[348] For example, by inhibiting CYP2D6,
paroxetine increases the steady-state plasma concentrations of
R-methadone in EMs but not in PMs. Genetically precipitated
drug interactions might render a standard opioid dose toxic.
Pharmacogenetics of CYP2D6 789
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1.10 Oral Antihyperglycaemic Drugs
Oral antihyperglycaemic drugs include sulphonylureas (e.g.
glipizide, glimepiride and glyburide) and biguanides (e.g. met-
formin, buformin and phenformin), which are currently used in
the treatment of type 2 diabetesmellitus.[403] The bioavailability
of biguanides ranges from 40% to 60%. Among biguanides,
phenformin undergoes partial hepatic hydroxylation and is
excreted in both the urine and faeces, whereas metformin and
buformin are not metabolized and are excreted in the urine.[403]
Fatal lactic acidosis may develop in patients receiving phen-
formin and thus it has been withdrawn in the US.
1.10.1 Phenformin
Phenformin is a biguanide antidiabetic agent and has been
withdrawn from the market because of severe lactic acidosis,
which is fatal in ~50% of cases.[404] This drug has been replacedby
metformin in clinical practice. Phenformin is excreted largely
unchanged through the kidneys (~50–86%), with partial meta-
bolism mediated by polymorphic CYP2D6 via p-hydroxylation
(see supplementary figure 52, Supplemental Digital Content
1).[405,406] 4-Hydroxylated phenformin can be further conjugated.
Phenformin and its 4-hydroxylated metabolite in a free or con-
jugated form are excreted into the urine. Phenformin 4-hydro-
xylation is highly variable (184-fold) and cosegregated with
debrisoquine MRs.[405,406] 4-Hydroxyphenformin is not detected
in PMs.[407] Risk factors for phenformin-induced lactic acidosis
include renal, liver or cardiac disease, alcoholism and the
CYP2D6 PM phenotype.[404,408] Increased phenformin plasma
concentrations have been observed in patients with lactic acido-
sis,[404] and the AUC of phenformin is ~1.4-fold higher and lac-
tate concentrations greater in PMs after a single dose.[409]
However, there is weak evidence directly implicating the
CYP2D6 phenotype as a cause or a primary risk factor,[410,411]
and the risk of developing lactic acidosis may be related more to
other factors than to the CYP2D6 PM phenotype status.
1.11 Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are struc-
turally different compounds that interact with intracellular
estrogen receptors in target organs as estrogen agonists and
antagonists.[412,413] SERMs currently approved for use in pa-
tients include tamoxifen, raloxifene and toremifene. Tamox-
ifen, a triphenylethyleneamine derivative, is one of the most
widely used SERMs for the treatment of hormone-sensitive and
estrogen receptor-positive breast cancer.[414,415] Other triphe-
nylethylene SERMs, analogues of tamoxifen, have been in-
vestigated for breast cancer prevention and/or treatment,
including droloxifene (3-hydroxytamoxifen), idoxifene (pyrro-
lidino-4-iodotamoxifen) and ospemifene. Several SERMs
are metabolized by CYP2D6. Tamoxifen is activated by
CYP2D6[416-420] and droloxifene undergoes ortho hydorxyla-
tion by CYP2D6 and 3A4 to 3,4-dihydroxytamoxifen ca-
techol.[421] Enclomifene, the more active isomer of clomifene, is
mainly metabolized by CYP2D6.[422]
1.11.1 Tamoxifen
Tamoxifen was first approved in 1977 by the FDA for the
treatment of metastatic breast cancer and more recently for
adjuvant treatment of breast cancer. Tamoxifen undergoes
extensive phase I and phase II metabolism,[423] and the con-
centrations of tamoxifen and its metabolites in humans vary
widely in patients. Tamoxifen undergoes extensive oxidation,
predominantly by various CYP isoenzymes, to several primary
and secondary metabolites (see supplementary figure 53, Sup-
plemental Digital Content 1). The formation of 4-OH-tamoxifen
from tamoxifen is mainly by CYP2D6,[417-420,424] with contribu-
tions from CYP2C9 and 3A4.[420] Although 4-hydroxylation of
tamoxifen represents <10% of overall tamoxifen oxidation and 4-
OH-tamoxifen is a relatively minor metabolite, 4-OH-tamoxifen
possesses 100-fold greater affinity for the estrogen receptor and
30- to 100-fold greater potency in inhibiting estrogen-dependent
cell proliferation than tamoxifen.[425] N-desmethyltamoxifen is
para-hydroxylated mainly by CYP2D6 to its most abundant and
therapeutically active metabolite endoxifen (4-OH-N-des-
methyltamoxifen) [see supplementary figure 53, Supplemental
Digital Content 1].[417-420,424] Endoxifen can also be generated
from 4-hydroxytamoxifen via N-demethylation,[416] but the
4-hydroxylation of N-desmethyltamoxifen by CYP2D6 appears
to be the major source of endoxifen production in vivo. Overall,
CYP2D6 plays a critical role in the activation of tamoxifen
to endoxifen by sequential N-demethylation and 4-hydroxyla-
tion.[416-420] The adverse-event profile of tamoxifen includes ve-
nous thrombosis, endometrial cancer and, most commonly, hot
flushes, which are often treated with an SSRI antidepressant.
Endoxifen is considered to be more important than 4-OH-
tamoxifen in terms of the relative contribution to the overall
anticancer effect of tamoxifen. Steady-state plasma endoxifen
concentrations are 5- to 10-fold higher than 4-OH-tamox-
ifen.[418,426] Women receiving tamoxifen treatment who either
carry genetic variants associated with low or absent CYP2D6
activity or who receive concomitant drugs known to inhibit
CYP2D6 activity have significantly lower concentrations of
endoxifen.[418,426] Concomitant use of paroxetine is associated
with lower endoxifen plasma concentrations, with the magni-
790 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
tude of this difference being dependent on the CYP2D6 geno-
type. Thus, interindividual differences in the formation of these
activemetabolites could be an important source of variability in
the response to tamoxifen.
Because of the important role of CYP2D6 in tamoxifen
metabolism and activation, PMs are likely to exhibit ther-
apeutic failure and UMs are likely to experience adverse effects
and toxicities. PMs have been shown to have lower endoxifen
concentrations than EMs.[427] Tamoxifen-treated cancer pa-
tients carrying CYP2D6*4, *5, *10 or *41 associated with sig-
nificantly decreased formation of antiestrogenic metabolites
had significantly more recurrences of breast cancer and shorter
relapse-free periods.[426,428-432] In the study by Goetz et al.[432]
of 256 cancer patients treated with tamoxifen, patients with the
CYP2D6*4/*4 genotype (n = 13) had poorer clinical outcomes
with shorter relapse-free and disease-free survival, and the
5-year disease-free survival for CYP2D6*4/*4 homozygous
patients was only 46%, compared with 83% for patients who
were not carriers of the CYP2D6*4 allele. None of the women
with the *4/*4 genotype experienced moderate or severe hot
flashes, compared with 20% of the women with either the *1/*4or *1/*1 genotypes. However, this study did not measure the
plasma concentrations of 4-OH-tamoxifen and endoxifen.
In a study of 206 cancer patients receiving adjuvant ta-
moxifen monotherapy, tamoxifen-treated patients carrying the
CYP2D6*4, *5, *10 or *41 alleles associated with impaired
formation of antiestrogenic metabolites had significantly more
recurrences of breast cancer, shorter relapse-free periods and
lower event-free survival rates than patients with functional
CYP2D6 alleles.[428] The plasma concentrations of endoxifen
and 4-OH-tamoxifen were not determined in these patients.
In Chinese breast cancer patients treated with tamoxifen
(n= 152), serum4-OH-tamoxifen concentrationswere significantly
lower inwomenwhowere homozygous forCYP2D6*10 than inthose with the homozygous wild-type.[433] Patients carrying
CYP2D6*10/*10 had lower disease-free survival rates than
those with the *1/*10 and *1/*1 genotypes. In Japanese breast
cancer patients (n = 67), the elevated risk of recurrence within
10 years after the operation seemed to be dependent on the
CYP2D6*10 allele.[434] Patients who were homozygous for the
CYP2D6*10 allele had a significantly higher incidence of re-
currence than those who were homozygous for the wild-type
CYP2D6*1 allele. After adjustment for other prognosis factors,
patients with the CYP2D6*10/*10 genotype had significantly
shorter recurrence-free survival than patients with CYP-
2D6*1/*1.[434]
In a study ofKorean breast cancer patients (n = 202), carriers
of nonfunctional CYP2D6*10/*10 (n = 49) demonstrated sig-
nificantly lower steady-state plasma concentrations of en-
doxifen and 4-OH-tamoxifen than those with other genotypes
(n = 153) [endoxifen 7.9 vs 18.9 ng/mL; 4-OH-tamoxifen 1.5 vs
2.6 ng/mL].[435] In this study, there was a correlation between
the CYP2D6 genotype and the number of disease sites. The
median time to progression for patients receiving tamoxifen
was shorter in those carrying CYP2D6*10/*10 than in the
others (5.0 vs 21.8 months).
PMs may also have an increased risk of developing adverse
effects during tamoxifen treatment, which include venous
thrombosis and endometrial cancer. However, the evidence is
lacking.
Many studies have identified the geneticCYP2D6 status as an
independent predictor for the outcome of tamoxifen treatment in
women with breast cancer, but others did not observe this re-
lationship.[436-438] Discrepant results may be explained by differ-
ences in study designs, including size, different genetic models for
the assessment of phenotypes, or stratification effects.
Although themetabolism of tamoxifen to 4-OH-tamoxifen is
catalysed by multiple enzymes, endoxifen is formed pre-
dominantly by CYP2D6-mediated oxidation of N-desmethyl-
tamoxifen. There is a clear gene-concentration effect for the
formation of endoxifen and 4-OH-tamoxifen. Currently avail-
able clinical findings strongly suggest that CYP2D6 status is an
independent predictor of the outcome of tamoxifen treat-
ment.[439-441] CYP2D6*10/*10 is associated with lower steady-
state plasma concentrations of active tamoxifen metabolites,
which could possibly influence the clinical outcome of tamox-
ifen in Asian breast cancer patients. Thus, more favourable
tamoxifen treatment seems to be feasible through a priori ge-
netic assessment of CYP2D6, and proper dose adjustment may
be needed when the CYP2D6 genotype is determined in a pa-
tient. Further studies are needed in women receiving tamoxifen
to fully define the effect of CYP2D6 genetic polymorphisms
and medications that inhibit CYP2D6 on tamoxifen response.
2. Conclusions and Future Perspectives
In conclusion, a number of allelic variants of the human
CYP2D6 gene have been defined, which may result in complete
absence of enzyme activity, reduced activity, normal activity
or even increased activity phenotypically. Among the most
important variants areCYP2D6*2, *3, *4, *5, *10, *17 and *41.In addition, a large number of low-frequency alleles of
CYP2D6 associated with the PM phenotype have been identi-
fied. Rearrangements within the gene CYP2D locus have re-
sulted in variant alleles harbouring two or multiple CYP2D6
genes, deletion of the entire gene, or creation of fused genes.
Pharmacogenetics of CYP2D6 791
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
Unlike other CYP isoenzymes, CYP2D6 is not inducible, and
thus genetic mutations are largely responsible for the inter-
individual variation in enzyme expression and activity. This
often presents a barrier to attaining optimal therapeutic con-
centrations.
It is clear that drugs that are substrates for CYP2D6 can
exhibit a large interindividual variation in their metabolism as a
result of polymorphisms in CYP2D6. Variation in CYP2D6
activity has important therapeutic consequences and can play
a significant role in the development of therapeutic failure or
adverse events in susceptible individuals. CYP2D6 poly-
morphisms are likely to become increasingly important in the
coming years as an increasing number of patients are prescribed
multiple drugs, a proportion of which are likely to be meta-
bolized by this isoenzyme.
Drugs that are most affected by CYP2D6 polymorphisms
are commonly those in which CYP2D6 represents a substantial
metabolic pathway either in the activation to form active me-
tabolites or in the clearance of the agent. However, such
a functional impact is substrate-dependent. For example,
CYP2D6*17 is generally considered to be an allele with reducedfunction, but it displays remarkable variability in activity to-
ward substrates, including dextromethorphan, risperidone,
codeine and haloperidol.[442] On the other hand, it is expected
that for drugs that are metabolized by CYP2D6 to a minor
extent (e.g. chlorpromazine), CYP2D6 mutations would not
alter their clearance significantly.
Phenotype prediction based on the genotype of CYP2D6 is
important in clinical practice. Several psychiatric hospitals have
already adopted CYP2D6 testing before treating a patient with
antidepressant or antipsychotic drug therapy. However, the
large number of allelic variants and even larger number of
potential combinations of these alleles certainly challenge our
phenotype prediction. The clinical phenotype of CYP2D6
polymorphisms is variable, depending on a number of factors
associated with the drug, patients, disease and other factors.
This makes prediction of the phenotype more difficult. Im-
portant factors affecting the phenotype include the extent of
CYP2D6-mediated metabolism, the activity of the parent drug
and its metabolites, and the overall contribution of the
CYP2D6-dependent pathway to the clearance of the drug from
the body. Furthermore, the therapeutic index of the drug, the
possible saturation of the CYP2D6-dependent pathway, the
contribution of other pathways of elimination, and coadmi-
nistered drugs need to be considered when performing pheno-
type prediction in a clinical setting.
Traditionally, the phenotype of CYP2D6 is defined as PM,
IM, EM andUM,which is largely dependent on ‘the number of
active genes’. The substantial overlap among the phenotypes –
in particular between IM and EM and between EM and UM –
reduces its value in practical applications. The determined
phenotype data are highly variable within a given ethnic group
and become more variable across ethnic groups, which often
cover 1–2 orders of magnitude.[443] Thus a few additional sys-
tems have been proposed to establish and predict more reliable
genotype-phenotype relationships. Steimer et al.[444] applied the
concept of the ‘semiquantitative gene dose’, which defined three
categories for functional, reduced and nonfunctional alleles
based on the relationship of the functional gene dose and
steady-state plasma amitriptyline or nortriptyline concentra-
tions in a cohort of 50 Caucasians. When this model was used
for venlafaxine, fluoxetine and risperidone, the phenotype
prediction rate was only slightly lower than the MR ap-
proach.[445] However, this concept has not been validated in
large study populations, in other ethnic groups, or for other
drugs that are mainly metabolized by CYP2D6. Recently,
Gaedigk et al.[446] proposed a 6-grade ‘activity score’ (grade 0,
0.5, 1, 1.5, 2 and >2) approach for phenotype prediction in
Caucasians and African Americans. The prediction appears to
be more accurate if ethnicity is taken into account. Ethnicity
and genotype as indicator variables explained 60%, whereas
ethnicity and activity score as indicators explained 59% of the
variability of MRs when dextromethorphan was used as a
probe. However, this activity score approach has not been
further validated in Asians, and there is limited value in clinical
practice when urinary data must be obtained.
CYP2D6 genotypes can readily be determinedwith currently
available commercial genotyping techniques. The genotype can
usually be unambiguously assigned on the basis of analysis of
approximately 20–25 polymorphic sites. However, some in-
dividuals show a phenotype that is discordant with their de-
termined genotype. Most of these unusual cases are PMs but
are carrying at least one functional or reduced-function allele
indicating an EM or IM phenotype. Subsequent studies of such
cases have led to identification of novel alleles such as
CYP2D6*36, *40 and *42 in African Americans[447-449] and
CYP2D6*21 and *44 in Japanese.[450]
Ethnicity must be considered when the genotyping test is
performed, because there are considerable differences in the
distribution of the most common alleles of CYP2D6 among
various ethnic groups.[451] For Caucasian subjects, assessment
of the most common alleles that result in loss of function would
require testing forCYP2D6*4 and should include the *3, *5, *6,*10 and *41 alleles. Determination of *10 and *17 would be
critical for prediction of the phenotype in Asians and Africans,
respectively.
792 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
The structure of human CYP2D6 has been recently de-
termined,[452] which may provide insights into the complex
genotype-phenotype relationship and ligand-enzyme interac-
tions of CYP2D6.[453] The 2D6 structure has a well defined
active site cavity above the heme group with a volume of ~540A3. Many important residues in CYP2D6 have been implicated
in substrate recognition and binding, including Asp301,
Glu216, Phe483 and Phe120.[452] The heme is anchored in the
binding site by hydrogen bonding interactions with the side
chains of Arg101, Trp128, Arg132, His376, Ser437 andArg441.
The importance of some of these residues has been confirmed
by site-directed mutagenesis studies.[454,455] However, there are
no natural mutations in many of these residues, and thus
functional studies are needed.
To date, the functional impact of most CYP2D6 alleles has
not been systematically assessed for most clinically important
drugs that are mainly metabolized by CYP2D6, though some
initial evidence has been identified for a very limited number of
drugs. The majority of reported in vivo pharmacogenetic data
on CYP2D6 are from single-dose and steady-state pharmaco-
kinetic studies for a small number of drugs. Pharmacodynamic
data on CYP2D6 polymorphisms are scanty for most drugs
studied. Given that genotyping testing for CYP2D6 is not
routinely performed in clinical practice and there is uncertainty
regarding genotype-phenotype, gene-concentration and gene-
dose relationships, further prospective studies on the clinical
impact of CYP2D6-dependent metabolism of drugs are war-
ranted in large cohorts.
Acknowledgements
No sources of funding were used to assist in the preparation of this
review. The author has no conflicts of interest that are directly relevant to
the content of this review.
References1. Zhou S-F. Polymorphism of human cytochrome P450 2D6 and its clinical
significance: Part I. Clin Pharmacokinet 2009; 48: 689-723
2. BertilssonL.Metabolismof antidepressant andneuroleptic drugsby cytochrome
P450s: clinical and interethnic aspects. Clin Pharmacol Ther 2007; 82: 606-9
3. Hollister LE. Tricyclic antidepressants (first of two parts). NEngl JMed 1978;
299: 1106-9
4. Mellstrom B, von Bahr C. Demethylation and hydroxylation of amitriptyline,
nortriptyline, and 10-hydroxyamitriptyline in human liver microsomes.
Drug Metab Dispos 1981; 9: 565-8
5. VenkatakrishnanK, VonMoltke LL,ObachRS, et al.Microsomal binding of
amitriptyline: effect on estimation of enzyme kinetic parameters in vitro.
J Pharmacol Exp Ther 2000; 293: 343-50
6. Venkatakrishnan K, Schmider J, Harmatz JS, et al. Relative contribution of
CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies.
J Clin Pharmacol 2001; 41: 1043-54
7. Olesen OV, Linnet K. Hydroxylation and demethylation of the tricyclic an-
tidepressant nortriptyline by cDNA-expressed human cytochrome P-450
isozymes. Drug Metab Dispos 1997; 25: 740-4
8. Breyer-Pfaff U. The metabolic fate of amitriptyline, nortriptyline and ami-
triptylinoxide in man. Drug Metab Rev 2004; 36: 723-46
9. Breyer-Pfaff U, Pfandl B, Nill K, et al. Enantioselective amitriptyline meta-
bolism in patients phenotyped for two cytochrome P450 isozymes. Clin
Pharmacol Ther 1992; 52: 350-8
10. Dahl ML, Nordin C, Bertilsson L. Enantioselective hydroxylation of nor-
triptyline in human liver microsomes, intestinal homogenate, and patients
treated with nortriptyline. Ther Drug Monit 1991; 13: 189-94
11. Nordin C, Bertilsson L. Active hydroxymetabolites of antidepressants: em-
phasis on E-10-hydroxy-nortriptyline. Clin Pharmacokinet 1995; 28: 26-40
12. Mellstrom B, Sawe J, Bertilsson L, et al. Amitriptyline metabolism: associa-
tion with debrisoquin hydroxylation in nonsmokers. Clin Pharmacol Ther
1986; 39: 369-71
13. Dahl ML, Bertilsson L, Nordin C. Steady-state plasma levels of nortriptyline
and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psy-
chopharmacology (Berl) 1996; 123: 315-9
14. Mellstrom B, Bertilsson L, Sawe J, et al. E- and Z-10-hydroxylation of nor-
triptyline: relationship to polymorphic debrisoquine hydroxylation. Clin
Pharmacol Ther 1981; 30: 189-93
15. Gram LF, Brosen K, Kragh-Sorensen P, et al. Steady-state plasma levels of
E- and Z-10-OH-nortriptyline in nortriptyline-treated patients: significance
of concurrent medication and the sparteine oxidation phenotype. Ther Drug
Monit 1989; 11: 508-14
16. Dalen P, Dahl ML, Bernal Ruiz ML, et al. 10-Hydroxylation of nortriptyline
in White persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin
Pharmacol Ther 1998; 63: 444-52
17. Yue QY, Zhong ZH, Tybring G, et al. Pharmacokinetics of nortriptyline and
its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 geno-
types. Clin Pharmacol Ther 1998; 64: 384-90
18. Morita S, Shimoda K, Someya T, et al. Steady-state plasma levels of
nortriptyline and its hydroxylated metabolites in Japanese patients: impact
of CYP2D6 genotype on the hydroxylation of nortriptyline. J Clin Psycho-
pharmacol 2000; 20: 141-9
19. Halling J, Weihe P, Brosen K. The CYP2D6 polymorphism in relation to the
metabolism of amitriptyline and nortriptyline in the Faroese population. Br
J Clin Pharmacol 2008; 65: 134-8
20. Steimer W, Zopf K, von Amelunxen S, et al. Amitriptyline or not, that is the
question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies
patients with low or high risk for side effects in amitriptyline therapy.
Clin Chem 2005; 51: 376-85
21. Roberts RL, Mulder RT, Joyce PR, et al. No evidence of increased adverse
drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with
fluoxetine or nortriptyline. Hum Psychopharmacol 2004; 19: 17-23
22. van der Kuy PH, Hooymans PM. Nortriptyline intoxication induced by ter-
binafine. BMJ 1998; 316: 441
23. Bertilsson L, Aberg-Wistedt A, Gustafsson LL, et al. Extremely rapid
hydroxylation of debrisoquine: a case report with implication for treatment
with nortriptyline and other tricyclic antidepressants. Ther Drug Monit
1985; 7: 478-80
24. Peters II MD, Davis SK, Austin LS. Clomipramine: an antiobsessional tri-
cyclic antidepressant. Clin Pharm 1990; 9: 165-78
25. Balant-Gorgia AE, Gex-Fabry M, Balant LP. Clinical pharmacokinetics of
clomipramine. Clin Pharmacokinet 1991; 20: 447-62
26. Nielsen KK, Flinois JP, Beaune P, et al. The biotransformation of clomi-
pramine in vitro, identification of the cytochrome P450s responsible for the
separate metabolic pathways. J Pharmacol Exp Ther 1996; 277: 1659-64
Pharmacogenetics of CYP2D6 793
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
27. Nielsen KK, Brosen K, Hansen MG, et al. Single-dose kinetics of clomipra-
mine: relationship to the sparteine and S-mephenytoin oxidation poly-
morphisms. Clin Pharmacol Ther 1994; 55: 518-27
28. Nielsen KK, BrosenK, GramLF. Steady-state plasma levels of clomipramine
and its metabolites: impact of the sparteine/debrisoquine oxidation poly-
morphism. Danish University Antidepressant Group. Eur J Clin Pharmacol
1992; 43: 405-11
29. Sindrup SH, Gram LF, Skjold T, et al. Clomipramine vs desipramine vs
placebo in the treatment of diabetic neuropathy symptoms: a double-blind
cross-over study. Br J Clin Pharmacol 1990; 30: 683-91
30. Pinder RM, Brogden RN, Speight TM, et al. Doxepin up-to-date: a review of
its pharmacological properties and therapeutic efficacy with particular re-
ference to depression. Drugs 1977; 13: 161-218
31. Shu YZ, Hubbard JW, Cooper JK, et al. The identification of urinary me-
tabolites of doxepin in patients. Drug Metab Dispos 1990; 18: 735-41
32. Haritos VS, Ghabrial H, Ahokas JT, et al. Role of cytochrome P450 2D6
(CYP2D6) in the stereospecific metabolism of E- and Z-doxepin. Pharma-
cogenetics 2000; 10: 591-603
33. Hartter S, Tybring G, Friedberg T, et al. TheN-demethylation of the doxepin
isomers is mainly catalyzed by the polymorphic CYP2C19. PharmRes 2002;
19: 1034-7
34. Kirchheiner J, Meineke I, Muller G, et al. Contributions of CYP2D6,
CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in
healthy volunteers. Pharmacogenetics 2002; 12: 571-80
35. Koski A, Ojanpera I, Sistonen J, et al. A fatal doxepin poisoning associated
with a defective CYP2D6 genotype. Am J Forensic Med Pathol 2007; 28:
259-61
36. Sallee FR, Pollock BG. Clinical pharmacokinetics of imipramine and desi-
pramine. Clin Pharmacokinet 1990; 18: 346-64
37. Lemoine A, Gautier JC, Azoulay D, et al. Major pathway of imipramine
metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human
liver. Mol Pharmacol 1993; 43: 827-32
38. Koyama E, Chiba K, Tani M, et al. Reappraisal of human CYP isoforms
involved in imipramineN-demethylation and 2-hydroxylation: a study using
microsomes obtained from putative extensive and poor metabolizers of
S-mephenytoin and eleven recombinant human CYPs. J Pharmacol Exp
Ther 1997; 281: 1199-210
39. BrosenK, Zeugin T,MeyerUA.Role of P450IID6, the target of the sparteine-
debrisoquin oxidation polymorphism, in themetabolism of imipramine. Clin
Pharmacol Ther 1991; 49: 609-17
40. Nakajima M, Tanaka E, Kobayashi T, et al. Imipramine N-glucuronidation
in human liver microsomes: biphasic kinetics and characterization of UDP-
glucuronosyltransferase isoforms. Drug Metab Dispos 2002; 30: 636-42
41. Koyama E, Kikuchi Y, Echizen H, et al. Simultaneous high-performance
liquid chromatography-electrochemical detection determination of imipra-
mine, desipramine, their 2-hydroxylated metabolites, and imipramine
N-oxide in human plasma and urine: preliminary application to oxidation
pharmacogenetics. Ther Drug Monit 1993; 15: 224-35
42. Brosen K, Otton SV, Gram LF. Imipramine demethylation and hydroxyla-
tion: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther
1986; 40: 543-9
43. Spina E, Steiner E, Ericsson O, et al. Hydroxylation of desmethylimipramine:
dependence on the debrisoquin hydroxylation phenotype. Clin Pharmacol
Ther 1987; 41: 314-9
44. Steiner E, Spina E. Differences in the inhibitory effect of cimetidine on desi-
pramine metabolism between rapid and slow debrisoquin hydroxylators.
Clin Pharmacol Ther 1987; 42: 278-82
45. Spina E, Gitto C, Avenoso A, et al. Relationship between plasma desipramine
levels, CYP2D6 phenotype and clinical response to desipramine: a pro-
spective study. Eur J Clin Pharmacol 1997; 51: 395-8
46. Shimoda K, Morita S, Hirokane G, et al. Metabolism of desipramine in
Japanese psychiatric patients: the impact of CYP2D6 genotype on the
hydroxylation of desipramine. Pharmacol Toxicol 2000; 86: 245-9
47. Brosen K, Klysner R, Gram LF, et al. Steady-state concentrations of imi-
pramine and its metabolites in relation to the sparteine/debrisoquine poly-
morphism. Eur J Clin Pharmacol 1986; 30: 679-84
48. Sindrup SH, Brosen K, Gram LF. Nonlinear kinetics of imipramine in low
and medium plasma level ranges. Ther Drug Monit 1990; 12: 445-9
49. Schenk PW, van Fessem MA, Verploegh-Van Rij S, et al. Association of
graded allele-specific changes in CYP2D6 function with imipramine dose
requirement in a large group of depressed patients. Mol Psychiatry 2008; 13:
597-605
50. Pinder RM, Brogden RN, Speight TM, et al. Maprotiline: a review of its
pharmacological properties and therapeutic efficacy in mental depressive
states. Drugs 1977; 13: 321-52
51. Brachtendorf L, Jetter A, Beckurts KT, et al. Cytochrome P450 enzymes
contributing to demethylation of maprotiline in man. Pharmacol Toxicol
2002; 90: 144-9
52. Breyer-Pfaff U, Kroeker M, Winkler T, et al. Isolation and identification of
hydroxylated maprotiline metabolites. Xenobiotica 1985; 15: 57-66
53. Hartter S, Wetzel H, Hammes E, et al. Inhibition of antidepressant
demethylation and hydroxylation by fluvoxamine in depressed patients.
Psychopharmacology (Berl) 1993; 110: 302-8
54. Normann C, Lieb K, Walden J. Increased plasma concentration of mapro-
tiline by coadministration of risperidone. J Clin Psychopharmacol 2002; 22:
92-4
55. Konig F, Wolfersdorf M, Loble M, et al. Trimipramine and maprotiline
plasma levels during combined treatment with moclobemide in therapy-re-
sistant depression. Pharmacopsychiatry 1997; 30: 125-7
56. Gram LF, Guentert TW, Grange S, et al. Moclobemide, a substrate of
CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel
study. Clin Pharmacol Ther 1995; 57: 670-7
57. Firkusny L,Gleiter CH.Maprotilinemetabolism appears to co-segregate with
the genetically-determined CYP2D6 polymorphic hydroxylation of debri-
soquine. Br J Clin Pharmacol 1994; 37: 383-8
58. GastparM. Clinical originality and new biology of trimipramine. Drugs 1989;
38 Suppl. 1: 43-8; discussion 49-50
59. Bolaji OO, Coutts RT, Baker GB. Metabolism of trimipramine in vitro by
human CYP2D6 isozyme. Res Commun Chem Pathol Pharmacol 1993; 82:
111-20
60. Eap CB, Bender S, Gastpar M, et al. Steady state plasma levels of the en-
antiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19-
and CYP3A4/5-phenotyped patients. Ther Drug Monit 2000; 22: 209-14
61. Kirchheiner J, Muller G, Meineke I, et al. Effects of polymorphisms in
CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics.
J Clin Psychopharmacol 2003; 23: 459-66
62. Eap CB, Laurian S, Souche A, et al. Influence of quinidine on the pharma-
cokinetics of trimipramine and on its effect on the waking EEG of healthy
volunteers: a pilot study on two subjects. Neuropsychobiology 1992; 25:
214-20
63. Leinonen E, Koponen HJ, Lepola U. Paroxetine increases serum trimipra-
mine concentration: a report of two cases. Human Psychopharmacol Clin
Exp 2004; 10: 345-7
64. Musshoff F, Schmidt P, Madea B. Fatality caused by a combined trimipra-
mine-citalopram intoxication. Forensic Sci Int 1999; 106: 125-31
65. Caccia S. Metabolism of the newer antidepressants: an overview of the
pharmacological and pharmacokinetic implications. Clin Pharmacokinet
1998; 34: 281-302
66. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake in-
hibitors. Pharmacol Ther 2000; 85: 11-28
794 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
67. Preskorn SH. Clinically relevant pharmacology of selective serotonin re-
uptake inhibitors: an overview with emphasis on pharmacokinetics and ef-
fects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32 Suppl. 1:
1-21
68. Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethyla-
tion of venlafaxine in vitro by human liver microsomes and by microsomes
from cDNA-transfected cells: effect of metabolic inhibitors and SSRI anti-
depressants. Neuropsychopharmacology 1999; 20: 480-90
69. Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet
2007; 46: 281-90
70. Olesen OV, Linnet K. Studies on the stereoselective metabolism of citalopram
by human liver microsomes and cDNA-expressed cytochrome P450 en-
zymes. Pharmacology 1999; 59: 298-309
71. von Moltke LL, Greenblatt DJ, Giancarlo GM, et al. Escitalopram (S-
citalopram) and its metabolites in vitro: cytochromes mediating bio-
transformation, inhibitory effects, and comparison to R-citalopram. Drug
Metab Dispos 2001; 29: 1102-9
72. Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram
enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes.
Br J Clin Pharmacol 2003; 56: 415-21
73. Peters EJ, Slager SL, Kraft JB, et al. Pharmacokinetic genes do not influence
response or tolerance to citalopram in the STAR*D sample. PLoS ONE
2008; 3: e1872
74. Reis M, Lundmark J, Bengtsson F. Therapeutic drug monitoring of racemic
citalopram: a 5-year experience in Sweden, 1992-1997. Ther Drug Monit
2003; 25: 183-91
75. Figgitt DP, McClellan KJ. Fluvoxamine: an updated review of its use in the
management of adults with anxiety disorders. Drugs 2000; 60: 925-54
76. Wilde MI, Plosker GL, Benfield P. Fluvoxamine: an updated review of its
pharmacology, and therapeutic use in depressive illness. Drugs 1993; 46:
895-924
77. Spigset O, Granberg K, Hagg S, et al. Non-linear fluvoxamine disposition. Br
J Clin Pharmacol 1998; 45: 257-63
78. Perucca E, Gatti G, Spina E. Clinical pharmacokinetics of fluvoxamine. Clin
Pharmacokinet 1994; 27: 175-90
79. Spigset O, Axelsson S, Norstrom A, et al. The major fluvoxamine metabolite
in urine is formed by CYP2D6. Eur J Clin Pharmacol 2001; 57: 653-8
80. DeVane CL, Gill HS. Clinical pharmacokinetics of fluvoxamine: applications
to dosage regimen design. J Clin Psychiatry 1997; 58 Suppl. 5: 7-14
81. van Harten J. Overview of the pharmacokinetics of fluvoxamine. Clin
Pharmacokinet 1995; 29 Suppl. 1: 1-9
82. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug
interactions with second-generation antidepressants: an update. Clin Ther
2008; 30: 1206-27
83. WagnerW,Vause EW.Fluvoxamine: a review of global drug-drug interaction
data. Clin Pharmacokinet 1995; 29 Suppl. 1: 26-31; discussion 31-2
84. ChristensenM, TybringG,MiharaK, et al. Low daily 10-mg and 20-mg doses
of fluvoxamine inhibit the metabolism of both caffeine (cytochrome
P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther
2002; 71: 141-52
85. Suzuki Y, SawamuraK, Someya T. Polymorphisms in the 5-hydroxytryptamine
2A receptor and cytochrome P4502D6 genes synergistically predict fluvox-
amine-induced side effects in Japanese depressed patients. Neuropsycho-
pharmacology 2006; 31: 825-31
86. Kirchheiner J, Brosen K, Dahl ML, et al. CYP2D6 and CYP2C19 genotype-
based dose recommendations for antidepressants: a first step towards sub-
population-specific dosages. Acta Psychiatr Scand 2001; 104: 173-92
87. Mandrioli R, Forti GC, Raggi MA. Fluoxetine metabolism and pharmaco-
logical interactions: the role of cytochrome P450. Curr Drug Metab 2006; 7:
127-33
88. Margolis JM, O’Donnell JP, Mankowski DC, et al. (R)-, (S)-, and racemic
fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug
Metab Dispos 2000; 28: 1187-91
89. Ring BJ, Eckstein JA, Gillespie JS, et al. Identification of the human cyto-
chromes P450 responsible for in vitro formation of R- and S-norfluoxetine.
J Pharmacol Exp Ther 2001; 297: 1044-50
90. Hamelin BA, Turgeon J, Vallee F, et al. The disposition of fluoxetine but not
sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol
Ther 1996; 60: 512-21
91. Fjordside L, Jeppesen U, Eap CB, et al. The stereoselective metabolism of
fluoxetine in poor and extensive metabolizers of sparteine. Pharmacoge-
netics 1999; 9: 55-60
92. Scordo MG, Spina E, Dahl ML, et al. Influence of CYP2C9, 2C19 and 2D6
genetic polymorphisms on the steady-state plasma concentrations of the
enantiomers of fluoxetine and norfluoxetine. Basic Clin Pharmacol Toxicol
2005; 97: 296-301
93. Stedman CA, Begg EJ, Kennedy MA, et al. Cytochrome P450 2D6 genotype
does not predict SSRI (fluoxetine or paroxetine) induced hyponatraemia.
Hum Psychopharmacol 2002; 17: 187-90
94. Gunasekara NS, Noble S, Benfield P. Paroxetine: an update of its pharma-
cology and therapeutic use in depression and a review of its use in other
disorders. Drugs 1998; 55: 85-120
95. Bloomer JC, Woods FR, Haddock RE, et al. The role of cytochrome
P4502D6 in the metabolism of paroxetine by human liver microsomes.
Br J Clin Pharmacol 1992; 33: 521-3
96. Sindrup SH, Brosen K, Gram LF, et al. The relationship between paroxetine
and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51:
278-87
97. Sindrup SH, BrosenK,GramLF. Pharmacokinetics of the selective serotonin
reuptake inhibitor paroxetine: nonlinearity and relation to the sparteine
oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 288-95
98. Ozdemir V, Tyndale RF, Reed K, et al. Paroxetine steady-state plasma con-
centration in relation to CYP2D6 genotype in extensive metabolizers. J Clin
Psychopharmacol 1999; 19: 472-5
99. Lam YW, Gaedigk A, Ereshefsky L, et al. CYP2D6 inhibition by selective
serotonin reuptake inhibitors: analysis of achievable steady-state plasma
concentrations and the effect of ultrarapid metabolism at CYP2D6.
Pharmacotherapy 2002; 22: 1001-6
100. Charlier C, Broly F, Lhermitte M, et al. Polymorphisms in theCYP2D6 gene:
association with plasma concentrations of fluoxetine and paroxetine. Ther
Drug Monit 2003; 25: 738-42
101. Zourkova A, Hadasova E. Relationship between CYP 2D6 metabolic status
and sexual dysfunction in paroxetine treatment. J SexMarital Ther 2002; 28:
451-61
102. Murphy Jr GM, Kremer C, Rodrigues S, et al. Pharmacogenetics of anti-
depressant medication intolerance. Am J Psychiatry 2003; 160: 1830-5
103. Tanaka M, Kobayashi D, Murakami Y, et al. Genetic polymorphisms in the
5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea.
Int J Neuropsychopharmacol 2008; 11: 261-7
104. Pinder RM, Van Delft AM. The potential therapeutic role of the enantiomers
and metabolites of mianserin. Br J Clin Pharmacol 1983; 15 Suppl. 2:
269-76S
105. Delbressine LP, Moonen ME, Kaspersen FM, et al. Biotransformation of
mianserin in laboratory animals and man. Xenobiotica 1992; 22: 227-36
106. Stormer E, von Moltke LL, Shader RI, et al. Metabolism of the anti-
depressant mirtazapine in vitro: contribution of cytochromes P-450 1A2,
2D6, and 3A4. Drug Metab Dispos 2000; 28: 1168-75
107. Koyama E, Chiba K, TaniM, et al. Identification of human cytochrome P450
isoforms involved in the stereoselective metabolism of mianserin en-
antiomers. J Pharmacol Exp Ther 1996; 278: 21-30
Pharmacogenetics of CYP2D6 795
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
108. DahlML, TybringG, Elwin CE, et al. Stereoselective disposition ofmianserin
is related to debrisoquin hydroxylation polymorphism. Clin Pharmacol Ther
1994; 56: 176-83
109. Yasui N, Tybring G, Otani K, et al. Effects of thioridazine, an inhibitor of
CYP2D6, on the steady-state plasma concentrations of the enantiomers of
mianserin and its active metabolite, desmethylmianserin, in depressed
Japanese patients. Pharmacogenetics 1997; 7: 369-74
110. Sindrup SH, Tuxen C, Gram LF, et al. Lack of effect of mianserin on the
symptoms of diabetic neuropathy. Eur J Clin Pharmacol 1992; 43: 251-5
111. Tacke U, Leinonen E, Lillsunde P, et al. Debrisoquine hydroxylation phe-
notypes of patients with high versus low to normal serum antidepressant
concentrations. J Clin Psychopharmacol 1992; 12: 262-7
112. Begg EJ, Sharman JR, Kidd JE, et al. Variability in the elimination of
mianserin in elderly patients. Br J Clin Pharmacol 1989; 27: 445-51
113. Mihara K, Otani K, Tybring G, et al. The CYP2D6 genotype and plasma
concentrations of mianserin enantiomers in relation to therapeutic response
to mianserin in depressed Japanese patients. J Clin Psychopharmacol 1997;
17: 467-71
114. Anttila SA, Leinonen EV.A review of the pharmacological and clinical profile
of mirtazapine. CNS Drug Rev 2001; 7: 249-64
115. Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirta-
zapine. Clin Pharmacokinet 2000; 38: 461-74
116. Delbressine LP, Moonen ME, Kaspersen FM, et al. Pharmacokinetics and
biotransformation of mirtazapine in human volunteers. Clin Drug Investig
1998; 15: 45-55
117. Grasmader K, Verwohlt PL, Kuhn KU, et al. Population pharmacokinetic
analysis of mirtazapine. Eur J Clin Pharmacol 2004; 60: 473-80
118. Kirchheiner J, Henckel HB, Meineke I, et al. Impact of the CYP2D6 ultra-
rapid metabolizer genotype on mirtazapine pharmacokinetics and adverse
events in healthy volunteers. J Clin Psychopharmacol 2004; 24: 647-52
119. Brockmoller J, Meineke I, Kirchheiner J. Pharmacokinetics of mirtazapine:
enantioselective effects of theCYP2D6 ultra rapidmetabolizer genotype and
correlation with adverse effects. Clin Pharmacol Ther 2007; 81: 699-707
120. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and
therapeutic potential in depression. Drugs 1995; 49: 280-94
121. Ellingrod VL, Perry PJ. Venlafaxine: a heterocyclic antidepressant. Am J
Hosp Pharm 1994; 51: 3033-46
122. Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is cata-
lysed by CYP2D6. Br J Clin Pharmacol 1996; 41: 149-56
123. Lindh JD, Annas A, Meurling L, et al. Effect of ketoconazole on venlafaxine
plasma concentrations in extensive and poor metabolisers of debrisoquine.
Eur J Clin Pharmacol 2003; 59: 401-6
124. Lessard E, Yessine MA, Hamelin BA, et al. Influence of CYP2D6 activity on
the disposition and cardiovascular toxicity of the antidepressant agent
venlafaxine in humans. Pharmacogenetics 1999; 9: 435-43
125. Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and
CYP2D6 genotype. Ther Drug Monit 2000; 22: 202-8
126. Fukuda T, Nishida Y, Zhou Q, et al. The impact of the CYP2D6 and
CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese popu-
lation. Eur J Clin Pharmacol 2000; 56: 175-80
127. Eap CB, Lessard E, Baumann P, et al. Role of CYP2D6 in the stereoselective
disposition of venlafaxine in humans. Pharmacogenetics 2003; 13: 39-47
128. Whyte EM, Romkes M, Mulsant BH, et al. CYP2D6 genotype and venla-
faxine-XR concentrations in depressed elderly. Int JGeriatr Psychiatry 2006;
21: 542-9
129. Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical
effect of the antidepressant venlafaxine. J Clin PharmTher 2006; 31: 493-502
130. Hermann M, Hendset M, Fosaas K, et al. Serum concentrations of venla-
faxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenla-
faxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele. Eur J Clin
Pharmacol 2008; 64: 483-7
131. McAlpine DE, O’Kane DJ, Black JL, et al. Cytochrome P450 2D6 genotype
variation and venlafaxine dosage. Mayo Clin Proc 2007; 82: 1065-8
132. Xu ZH, Wang W, Zhao XJ, et al. Evidence for involvement of polymorphic
CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver mi-
crosomes. Br J Clin Pharmacol 1999; 48: 416-23
133. Bertilsson L, Mellstrom B, Sjokvist F, et al. Slow hydroxylation of nor-
triptyline and concomitant poor debrisoquine hydroxylation: clinical im-
plications. Lancet 1981; 1: 560-1
134. Bluhm RE, Wilkinson GR, Shelton R, et al. Genetically determined drug-
metabolizing activity and desipramine-associated cardiotoxicity: a case
report. Clin Pharmacol Ther 1993; 53: 89-95
135. Bertilsson L, Dahl ML, Sjoqvist F, et al. Molecular basis for rational mega-
prescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993;
341: 63
136. Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse
effects and nonresponse during treatment with antidepressants. A pilot
study. Clin Pharmacol Ther 2004; 75: 386-93
137. Kawanishi C, Lundgren S, Agren H, et al. Increased incidence of CYP2D6
gene duplication in patients with persistent mood disorders: ultrarapid
metabolism of antidepressants as a cause of nonresponse. A pilot study.
Eur J Clin Pharmacol 2004; 59: 803-7
138. Grasmader K, Verwohlt PL, Rietschel M, et al. Impact of polymorphisms of
cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations
and clinical effects of antidepressants in a naturalistic clinical setting. Eur J
Clin Pharmacol 2004; 60: 329-36
139. Bijl MJ, Visser LE, Hofman A, et al. Influence of the CYP2D6*4 poly-
morphism on dose, switching and discontinuation of antidepressants.
Br J Clin Pharmacol 2008; 65: 558-64
140. Kwadijk-de Gijsel S, Bijl MJ, Visser LE, et al. Variation in the CYP2D6 gene
is associated with a lower serum sodium concentration in patients on
antidepressants. Br J Clin Pharmacol 2009; 68: 221-5
141. Seeringer A, Kirchheiner J. Pharmacogenetics-guided dose modifications of
antidepressants. Clin Lab Med 2008; 28: 619-26
142. Lieberman JA, Bymaster FP, Meltzer HY, et al. Antipsychotic drugs: com-
parison in animal models of efficacy, neurotransmitter regulation, and
neuroprotection. Pharmacol Rev 2008; 60: 358-403
143. Worrel JA, Marken PA, Beckman SE, et al. Atypical antipsychotic agents:
a critical review. Am J Health Syst Pharm 2000; 57: 238-55
144. Vohora D. Atypical antipsychotic drugs: current issues of safety and efficacy
in the management of schizophrenia. Curr Opin Investig Drugs 2007; 8:
531-8
145. Moller HJ. Risperidone: a review. Expert Opin Pharmacother 2005; 6: 803-18
146. Bishara D, Taylor D. Upcoming agents for the treatment of schizophrenia:
mechanism of action, efficacy and tolerability. Drugs 2008; 68: 2269-92
147. Gardiner SJ, Begg EJ. Pharmacogenetics drug-metabolizing enzymes, and
clinical practice. Pharmacol Rev 2006; 58: 521-90
148. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6
(CYP2D6): clinical consequences, evolutionary aspects and functional
diversity. Pharmacogenom J 2005; 5: 6-13
149. Zhou SF, Di YM, Chan E, et al. Clinical pharmacogenetics and potential
application in personalized medicine. Curr Drug Metab 2008; 9: 738-84
150. Swainston Harrison T, Perry CM. Aripiprazole: a review of its use in schi-
zophrenia and schizoaffective disorder. Drugs 2004; 64: 1715-36
151. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical
antipsychotic drug with a unique and robust pharmacology. Neuropsycho-
pharmacology 2003; 28: 1400-11
796 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
152. Molden E, Lunde H, Lunder N, et al. Pharmacokinetic variability of ar-
ipiprazole and the active metabolite dehydroaripiprazole in psychiatric
patients. Ther Drug Monit 2006; 28: 744-9
153. KuboM, Koue T, Inaba A, et al. Influence of itraconazole co-administration
and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic
aripiprazole. Drug Metab Pharmacokinet 2005; 20: 55-64
154. Kim JR, Seo HB, Cho JY, et al. Population pharmacokinetic modelling of
aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric
patients. Br J Clin Pharmacol 2008; 66: 802-10
155. Koue T, Kubo M, Funaki T, et al. Nonlinear mixed effects model analysis of
the pharmacokinetics of aripiprazole in healthy Japanese males. Biol Pharm
Bull 2007; 30: 2154-8
156. Kubo M, Koue T, Maune H, et al. Pharmacokinetics of aripiprazole, a new
antipsychotic, following oral dosing in healthy adult Japanese volunteers:
influence of CYP2D6 polymorphism. DrugMetab Pharmacokinet 2007; 22:
358-66
157. Hendset M, HermannM, Lunde H, et al. Impact of theCYP2D6 genotype on
steady-state serum concentrations of aripiprazole and dehydroaripiprazole.
Eur J Clin Pharmacol 2007; 63: 1147-51
158. Oosterhuis M, Van De Kraats G, Tenback D. Safety of aripiprazole: high
serum levels in a CYP2D6 mutated patient. Am J Psychiatry 2007; 164: 175
159. Waade RB, Christensen H, Rudberg I, et al. Influence of comedication on
serum concentrations of aripiprazole and dehydroaripiprazole. Ther Drug
Monit 2009; 31: 233-8
160. Hartmann F, Gruenke LD, Craig JC, et al. Chlorpromazine metabolism in
extracts of liver and small intestine from guinea pig and from man. Drug
Metab Dispos 1983; 11: 244-8
161. Yoshii K, Kobayashi K, Tsumuji M, et al. Identification of human cyto-
chrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by
human liver microsomes. Life Sci 2000; 67: 175-84
162. Muralidharan G, Cooper JK, Hawes EM, et al. Quinidine inhibits the
7-hydroxylation of chlorpromazine in extensive metabolisers of debriso-
quine. Eur J Clin Pharmacol 1996; 50: 121-8
163. Sunwoo YE, Ryu J, Jung H, et al. Disposition of chlorpromazine in Korean
healthy subjects with CYP2D6 wild-type and *10B mutation [abstract]. Clin
Pharmacol Ther 2004; 73: PII-146
164. Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update. Clin Phar-
macokinet 1999; 37: 435-56
165. Yatham LN. The role of novel antipsychotics in bipolar disorders. J Clin
Psychiatry 2002; 63: 10-4
166. Tateishi T, Watanabe M, Kumai T, et al. CYP3A is responsible for N-deal-
kylation of haloperidol and bromperidol and oxidation of their reduced
forms by human liver microsomes. Life Sci 2000; 67: 2913-20
167. Kudo S, Odomi M. Involvement of human cytochrome P450 3A4 in reduced
haloperidol oxidation. Eur J Clin Pharmacol 1998; 54: 253-9
168. Pan LP, De Vriendt C, Belpaire FM. In-vitro characterization of the cyto-
chrome P450 isoenzymes involved in the back oxidation andN-dealkylation
of reduced haloperidol. Pharmacogenetics 1998; 8: 383-9
169. Kim YH, Cha IJ, Shim JC, et al. Effect of rifampin on the plasma con-
centration and the clinical effect of haloperidol concomitantly administered
to schizophrenic patients. J Clin Psychopharmacol 1996; 16: 247-52
170. Avenoso A, Spina E, Campo G, et al. Interaction between fluoxetine and
haloperidol: pharmacokinetic and clinical implications. Pharmacol Res
1997; 35: 335-9
171. Vandel S, Bertschy G, Baumann P, et al. Fluvoxamine and fluoxetine: in-
teraction studies with amitriptyline, clomipramine and neuroleptics in phe-
notyped patients. Pharmacol Res 1995; 31: 347-53
172. Ulrich S, Wurthmann C, Brosz M, et al. The relationship between serum
concentration and therapeutic effect of haloperidol in patients with acute
schizophrenia. Clin Pharmacokinet 1998; 34: 227-63
173. Lane HY, Hu OY, Jann MW, et al. Dextromethorphan phenotyping and
haloperidol disposition in schizophrenic patients. Psychiatry Res 1997; 69:
105-11
174. Llerena A, Alm C, Dahl ML, et al. Haloperidol disposition is dependent on
debrisoquine hydroxylation phenotype. Ther Drug Monit 1992; 14: 92-7
175. LlerenaA,DahlML, Ekqvist B, et al. Haloperidol disposition is dependent on
the debrisoquine hydroxylation phenotype: increased plasma levels of the
reduced metabolite in poor metabolizers. Ther Drug Monit 1992; 14: 261-4
176. Nyberg S, Farde L, Halldin C, et al. D2 dopamine receptor occupancy during
low-dose treatment with haloperidol decanoate. Am J Psychiatry 1995; 152:
173-8
177. Brockmoller J, Kirchheiner J, Schmider J, et al. The impact of the CYP2D6
polymorphism on haloperidol pharmacokinetics and on the outcome of
haloperidol treatment. Clin Pharmacol Ther 2002; 72: 438-52
178. Panagiotidis G, Arthur HW, Lindh JD, et al. Depot haloperidol treatment in
outpatients with schizophrenia on monotherapy: impact of CYP2D6 poly-
morphism on pharmacokinetics and treatment outcome. Ther Drug Monit
2007; 29: 417-22
179. Suzuki A, Otani K, Mihara K, et al. Effects of the CYP2D6 genotype on the
steady-state plasma concentrations of haloperidol and reduced haloperidol
in Japanese schizophrenic patients. Pharmacogenetics 1997; 7: 415-8
180. Mihara K, Suzuki A, Kondo T, et al. Effects of the CYP2D6*10 allele on the
steady-state plasma concentrations of haloperidol and reduced haloperidol
in Japanese patients with schizophrenia. Clin Pharmacol Ther 1999; 65:
291-4
181. Roh HK, Chung JY, Oh DY, et al. Plasma concentrations of haloperidol are
related to CYP2D6 genotype at low, but not high doses of haloperidol in
Korean schizophrenic patients. Br J Clin Pharmacol 2001; 52: 265-71
182. Park JY, Shon JH, Kim KA, et al. Combined effects of itraconazole and
CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharma-
codynamics of haloperidol in healthy subjects. J Clin Psychopharmacol
2006; 26: 135-42
183. Shimoda K, Morita S, Yokono A, et al. CYP2D6*10 alleles are not the de-
terminant of the plasma haloperidol concentrations in Asian patients. Ther
Drug Monit 2000; 22: 392-6
184. Ohnuma T, ShibataN,Matsubara Y, et al. Haloperidol plasma concentration
in Japanese psychiatric subjects with gene duplication of CYP2D6. Br J Clin
Pharmacol 2003; 56: 315-20
185. Pan L, Vander Stichele R, Rosseel MT, et al. Effects of smoking, CYP2D6
genotype, and concomitant drug intake on the steady state plasma
concentrations of haloperidol and reduced haloperidol in schizophrenic in-
patients. Ther Drug Monit 1999; 21: 489-97
186. Someya T, Suzuki Y, Shimoda K, et al. The effect of cytochrome P450 2D6
genotypes on haloperidol metabolism: a preliminary study in a psychiatric
population. Psychiatry Clin Neurosci 1999; 53: 593-7
187. Hartung B, Wada M, Laux G, et al. Perphenazine for schizophrenia.
Cochrane Database Syst Rev 2005; (1): CD003443
188. Olesen OV, Linnet K. Identification of the human cytochrome P450 isoforms
mediating in vitro N-dealkylation of perphenazine. Br J Clin Pharmacol
2000; 50: 563-71
189. Bertilsson L, Dahl ML, Ekqvist B, et al. Disposition of the neuroleptics
perphenazine, zuclopenthixol, and haloperidol cosegregates with poly-
morphic debrisoquine hydroxylation. Psychopharmacol Ser 1993; 10: 230-7
190. Dahl-Puustinen ML, Liden A, Alm C, et al. Disposition of perphenazine is
related to polymorphic debrisoquin hydroxylation in human beings. Clin
Pharmacol Ther 1989; 46: 78-81
191. Linnet K, Wiborg O. Steady-state serum concentrations of the neuroleptic
perphenazine in relation toCYP2D6 genetic polymorphism. Clin Pharmacol
Ther 1996; 60: 41-7
Pharmacogenetics of CYP2D6 797
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
192. Jerling M, Dahl ML, Aberg-Wistedt A, et al. The CYP2D6 genotype predicts
the oral clearance of the neuroleptic agents perphenazine and zuclo-
penthixol. Clin Pharmacol Ther 1996; 59: 423-8
193. Ozdemir V, Bertilsson L, Miura J, et al. CYP2D6 genotype in relation
to perphenazine concentration and pituitary pharmacodynamic tissue
sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.
Pharmacogenet Genomics 2007; 17: 339-47
194. Aklillu E, Kalow W, Endrenyi L, et al. CYP2D6 and DRD2 genes differen-
tially impact pharmacodynamic sensitivity and time course of prolactin re-
sponse to perphenazine. Pharmacogenet Genomics 2007; 17: 989-93
195. Bushe C, Shaw M, Peveler RC. A review of the association between anti-
psychotic use and hyperprolactinaemia. J Psychopharmacol 2008; 22: 46-55
196. O’Keane V. Antipsychotic-induced hyperprolactinaemia, hypogonadism and
osteoporosis in the treatment of schizophrenia. J Psychopharmacol 2008; 22:
70-5
197. Peveler RC, Branford D, Citrome L, et al. Antipsychotics and hyperpro-
lactinaemia: clinical recommendations. J Psychopharmacol 2008; 22: 98-103
198. Molitch ME. Drugs and prolactin. Pituitary 2008; 11: 209-18
199. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: me-
chanisms, clinical features and management. Drugs 2004; 64: 2291-314
200. Yu AM, Idle JR, Byrd LG, et al. Regeneration of serotonin from 5-methox-
ytryptamine by polymorphic human CYP2D6. Pharmacogenetics 2003; 13:
173-81
201. Ozdemir V, Naranjo CA, Herrmann N, et al. Paroxetine potentiates the
central nervous system side effects of perphenazine: contribution of cyto-
chrome P4502D6 inhibition in vivo. Clin Pharmacol Ther 1997; 62: 334-47
202. Pollock BG, Mulsant BH, Sweet RA, et al. Prospective cytochrome P450
phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull
1995; 31: 327-31
203. Fenton C, Scott LJ. Risperidone: a review of its use in the treatment of bipolar
mania. CNS Drugs 2005; 19: 429-44
204. Grant S, Fitton A. Risperidone: a review of its pharmacology and therapeutic
potential in the treatment of schizophrenia. Drugs 1994; 48: 253-73
205. Mannens G, Huang ML, Meuldermans W, et al. Absorption, metabolism,
and excretion of risperidone in humans. Drug Metab Dispos 1993; 21:
1134-41
206. Yasui-Furukori N, HidestrandM, Spina E, et al. Different enantioselective 9-
hydroxylation of risperidone by the two human CYP2D6 and CYP3A4
enzymes. Drug Metab Dispos 2001; 29: 1263-8
207. Spina E, Avenoso A, Facciola G, et al. Plasma concentrations of risperidone
and 9-hydroxyrisperidone: effect of comedication with carbamazepine or
valproate. Ther Drug Monit 2000; 22: 481-5
208. Jung SM, Kim KA, Cho HK, et al. Cytochrome P450 3A inhibitor itraco-
nazole affects plasma concentrations of risperidone and 9-hydro-
xyrisperidone in schizophrenic patients. Clin Pharmacol Ther 2005; 78: 520-8
209. Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new
and reference antipsychotic drugs: in vitro and in vivo receptor binding.
Psychopharmacology (Berl) 1996; 124: 57-73
210. Spina E, Avenoso A, Facciola G, et al. Plasma concentrations of risperidone
and 9-hydroxyrisperidone during combined treatment with paroxetine. Ther
Drug Monit 2001; 23: 223-7
211. Mannheimer B, Bahr CV, Pettersson H, et al. Impact of multiple inhibitors or
substrates of cytochrome P450 2D6 on plasma risperidone levels in patients
on polypharmacy. Ther Drug Monit. Epub 2008 Aug 23
212. Scordo MG, Spina E, Facciola G, et al. Cytochrome P450 2D6 genotype
and steady state plasma levels of risperidone and 9-hydroxyrisperidone.
Psychopharmacology (Berl) 1999; 147: 300-5
213. Bondolfi G, Eap CB, Bertschy G, et al. The effect of fluoxetine on the phar-
macokinetics and safety of risperidone in psychotic patients. Pharma-
copsychiatry 2002; 35: 50-6
214. Olesen OV, Licht RW, Thomsen E, et al. Serum concentrations and side
effects in psychiatric patients during risperidone therapy. Ther Drug Monit
1998; 20: 380-4
215. Nyberg S, Dahl ML, Halldin C. A PET study of D2 and 5-HT2 receptor
occupancy induced by risperidone in poor metabolizers of debrisoquin and
risperidone. Psychopharmacology (Berl) 1995; 119: 345-8
216. Roh HK, Kim CE, Chung WG, et al. Risperidone metabolism in relation to
CYP2D6*10 allele in Korean schizophrenic patients. Eur J Clin Pharmacol
2001; 57: 671-5
217. Guzey C, Aamo T, Spigset O. Risperidone metabolism and the impact of
being a cytochrome P450 2D6 ultrarapid metabolizer. J Clin Psychiatry
2000; 61: 600-1
218. De Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer
phenotype may be associated with risperidone adverse drug reactions and
discontinuation. J Clin Psychiatry 2005; 66: 15-27
219. Wojcikowski J, Maurel P, Daniel WA. Characterization of human cyto-
chrome P450 enzymes involved in the metabolism of the piperidine-type
phenothiazine neuroleptic thioridazine. Drug Metab Dispos 2006; 34: 471-6
220. LlerenaA, Berecz R, de laRubiaA, et al. Use of themesoridazine/thioridazineratio as a marker for CYP2D6 enzyme activity. Ther Drug Monit 2000; 22:
397-401
221. Berecz R, de la Rubia A, Dorado P, et al. Thioridazine steady-state plasma
concentrations are influenced by tobacco smoking and CYP2D6, but not by
the CYP2C9 genotype. Eur J Clin Pharmacol 2003; 59: 45-50
222. Eap CB, Guentert TW, Schaublin-Loidl M, et al. Plasma levels of the en-
antiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone,
and thioridazine 5-sulfoxide in poor and extensive metabolizers of dex-
tromethorphan and mephenytoin. Clin Pharmacol Ther 1996; 59: 322-31
223. LlerenaA, Berecz R, de laRubia A, et al. QTc interval lengthening is related to
CYP2D6 hydroxylation capacity and plasma concentration of thioridazine
in patients. J Psychopharmacol 2002; 16: 361-4
224. von Bahr C, Movin G, Nordin C, et al. Plasma levels of thioridazine and
metabolites are influenced by the debrisoquin hydroxylation phenotype.
Clin Pharmacol Ther 1991; 49: 234-40
225. Kumar A, Strech D. Zuclopenthixol dihydrochloride for schizophrenia.
Cochrane Database Syst Rev 2005; (4): CD005474
226. Dahl ML, Ekqvist B, Widen J, et al. Disposition of the neuroleptic zuclo-
penthixol cosegregates with the polymorphic hydroxylation of debrisoquine
in humans. Acta Psychiatr Scand 1991; 84: 99-102
227. Linnet K,WiborgO. Influence ofCYP2D6 genetic polymorphism on ratios of
steady-state serum concentration to dose of the neuroleptic zuclopenthixol.
Ther Drug Monit 1996; 18: 629-34
228. Jaanson P, Marandi T, Kiivet RA, et al. Maintenance therapy with zuclo-
penthixol decanoate: associations between plasma concentrations, neuro-
logical side effects and CYP2D6 genotype. Psychopharmacology (Berl)
2002; 162: 67-73
229. Ring BJ, Catlow J, Lindsay TJ, et al. Identification of the human cytochromes
P450 responsible for the in vitro formation of themajor oxidativemetabolites
of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 1996; 276:
658-66
230. OlesenOV, LinnetK. Contributions of five human cytochrome P450 isoforms
to the N-demethylation of clozapine in vitro at low and high concentrations.
J Clin Pharmacol 2001; 41: 823-32
231. Schaber G, Wiatr G, Wachsmuth H, et al. Isolation and identification of
clozapine metabolites in patient urine. Drug Metab Dispos 2001; 29: 923-31
232. Breyer-Pfaff U, Wachsmuth H. Tertiary N-glucuronides of clozapine and its
metabolite desmethylclozapine in patient urine. Drug Metab Dispos 2001;
29: 1343-8
233. Hagg S, Spigset O, Lakso HA, et al. Olanzapine disposition in humans is
unrelated toCYP1A2 andCYP2D6 phenotypes. Eur J Clin Pharmacol 2001;
57: 493-7
798 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
234. Carrillo JA, Herraiz AG, Ramos SI, et al. Role of the smoking-induced
cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state
concentration of olanzapine. J Clin Psychopharmacol 2003; 23: 119-27
235. MelkerssonKI, ScordoMG,GunesA, et al. Impact ofCYP1A2 andCYP2D6
polymorphisms on drug metabolism and on insulin and lipid elevations and
insulin resistance in clozapine-treated patients. J Clin Psychiatry 2007; 68:
697-704
236. Dettling M, Sachse C, Muller-Oerlinghausen B, et al. Clozapine-induced
agranulocytosis and hereditary polymorphisms of clozapine metabolizing
enzymes: no association with myeloperoxidase and cytochrome P4502D6.
Pharmacopsychiatry 2000; 33: 218-20
237. Uehlinger C, Crettol S, Chassot P, et al. Increased (R)-methadone plasma
concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped
patients. J Clin Psychopharmacol 2007; 27: 273-8
238. Plesnicar BK, Zalar B, Breskvar K, et al. The influence of the CYP2D6
polymorphism on psychopathological and extrapyramidal symptoms in the
patients on long-term antipsychotic treatment. J Psychopharmacol 2006; 20:
829-33
239. Chou WH, Yan FX, de Leon J, et al. Extension of a pilot study: impact from
the cytochrome P450 2D6 polymorphism on outcome and costs associated
with severe mental illness. J Clin Psychopharmacol 2000; 20: 246-51
240. Dahl ML. Cytochrome P450 phenotyping/genotyping in patients receiving
antipsychotics: useful aid to prescribing? Clin Pharmacokinet 2002; 41:
453-70
241. Otani K, Aoshima T. Pharmacogenetics of classical and new antipsychotic
drugs. Ther Drug Monit 2000; 22: 118-21
242. Patsopoulos NA, Ntzani EE, Zintzaras E, et al.CYP2D6 polymorphisms and
the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmaco-
genet Genomics 2005; 15: 151-8
243. Sjoqvist F, Eliasson E. The convergence of conventional therapeutic drug
monitoring and pharmacogenetic testing in personalized medicine: focus on
antidepressants. Clin Pharmacol Ther 2007; 81: 899-902
244. Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharma-
codynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002; 41:
719-39
245. Spaldin V, Madden S, Pool WF, et al. The effect of enzyme inhibition on the
metabolism and activation of tacrine by human liver microsomes. Br J Clin
Pharmacol 1994; 38: 15-22
246. Barner EL, Gray SL. Donepezil use in Alzheimer disease. Ann Pharmacother
1998; 32: 70-7
247. Bachus R, Bickel U, Thomsen T, et al. The O-demethylation of the anti-
dementia drug galanthamine is catalysed by cytochrome P450 2D6. Phar-
macogenetics 1999; 9: 661-8
248. Seltzer B. Donepezil: an update. Expert Opin Pharmacother 2007; 8: 1011-23
249. Varsaldi F, Miglio G, Scordo MG, et al. Impact of the CYP2D6 poly-
morphism on steady-state plasma concentrations and clinical outcome of
donepezil in Alzheimer’s disease patients. Eur J Clin Pharmacol 2006; 62:
721-6
250. Whitehead A, Perdomo C, Pratt RD, et al. Donepezil for the symptomatic
treatment of patients with mild to moderate Alzheimer’s disease: a meta-
analysis of individual patient data from randomised controlled trials. Int J
Geriatr Psychiatry 2004; 19: 624-33
251. Tiseo PJ, Perdomo CA, Friedhoff LT. Metabolism and elimination of 14C-
donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol
1998; 46 Suppl. 1: 19-24
252. Cacabelos R, Llovo R, Fraile C, et al. Pharmacogenetic aspects of therapy
with cholinesterase inhibitors: the role of CYP2D6 in Alzheimer’s disease
pharmacogenetics. Curr Alzheimer Res 2007; 4: 479-500
253. Pilotto A, Franceschi M, D’Onofrio G, et al. Effect of a CYP2D6 poly-
morphism on the efficacy of donepezil in patients with Alzheimer disease.
Neurology 2009; 73: 761-7
254. Gaedigk A, Ryder DL, Bradford LD, et al. CYP2D6 poor metabolizer status
can be ruled out by a single genotyping assay for the -1584G promoter
polymorphism. Clin Chem 2003; 49: 1008-11
255. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase
inhibitors and memantine in vascular dementia: a meta-analysis of rando-
mised controlled trials. Lancet Neurol 2007; 6: 782-92
256. Westra P, van Thiel MJ, Vermeer GA, et al. Pharmacokinetics of galantha-
mine (a long-acting anticholinesterase drug) in anaesthetized patients.
Br J Anaesth 1986; 58: 1303-7
257. Mannens GS, Snel CA, Hendrickx J, et al. The metabolism and excretion of
galantamine in rats, dogs, and humans. DrugMetab Dispos 2002; 30: 553-63
258. Corman SL, Fedutes BA, Culley CM.Atomoxetine: the first nonstimulant for
the management of attention-deficit/hyperactivity disorder. Am J Health
Syst Pharm 2004; 61: 2391-9
259. Simpson D, Plosker GL. Atomoxetine: a review of its use in adults with
attention deficit hyperactivity disorder. Drugs 2004; 64: 205-22
260. Ring BJ, Gillespie JS, Eckstein JA, et al. Identification of the human cyto-
chromes P450 responsible for atomoxetine metabolism. DrugMetab Dispos
2002; 30: 319-23
261. Farid NA, Bergstrom RF, Ziege EA, et al. Single-dose and steady-state
pharmacokinetics of tomoxetine in normal subjects. J Clin Pharmacol 1985;
25: 296-301
262. Paulzen M, Clement HW, Grunder G. Enhancement of atomoxetine serum
levels by co-administration of paroxetine. Int J Neuropsychopharmacol
2008; 11: 289-91
263. Sauer JM, Ponsler GD, Mattiuz EL, et al. Disposition and metabolic fate of
atomoxetine hydrochloride: the role of CYP2D6 in human disposition and
metabolism. Drug Metab Dispos 2003; 31: 98-107
264. Cui YM, Teng CH, Pan AX, et al. Atomoxetine pharmacokinetics in healthy
Chinese subjects and effect of the CYP2D6*10 allele. Br J Clin Pharmacol
2007; 64: 445-9
265. Shen H, He MM, Liu H, et al. Comparative metabolic capabilities and in-
hibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab
Dispos 2007; 35: 1292-300
266. Michelson D, Read HA, Ruff DD, et al. CYP2D6 and clinical response to
atomoxetine in children and adolescents with ADHD. J Am Acad Child
Adolesc Psychiatry 2007; 46: 242-51
267. Trzepacz PT, Williams DW, Feldman PD, et al. CYP2D6 metabolizer status
and atomoxetine dosing in children and adolescents with ADHD. Eur
Neuropsychopharmacol 2008; 18: 79-86
268. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of
children and adolescents with attention-deficit/hyperactivity disorder:
a randomized, placebo-controlled, dose-response study. Pediatrics 2001;
108: E83
269. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of
children and adolescents with ADHD. J Clin Psychiatry 2002; 63 Suppl. 12:
50-5
270. Tamayo JM, Pumariega A, Rothe EM, et al. Latino versus Caucasian re-
sponse to atomoxetine in attention-deficit/hyperactivity disorder. J Child
Adolesc Psychopharmacol 2008; 18: 44-53
271. Baskys A, Hou AC. Vascular dementia: pharmacological treatment
approaches and perspectives. Clin Interv Aging 2007; 2: 327-35
272. Winblad B, Fioravanti M, Dolezal T, et al. Therapeutic use of nicergoline.
Clin Drug Investig 2008; 28: 533-52
273. ArcamoneF,Glasser AG,Grafnetterova J, et al. Studies on themetabolism of
ergoline derivatives: metabolism of nicergoline in man and in animals.
Biochem Pharmacol 1972; 21: 2205-13
274. Bottiger Y, Dostert P, Benedetti MS, et al. Involvement of CYP2D6 but not
CYP2C19 in nicergoline metabolism in humans. Br J Clin Pharmacol 1996;
42: 707-11
Pharmacogenetics of CYP2D6 799
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
275. Wefer J, Truss MC, Jonas U. Tolterodine: an overview. World J Urol 2001;
19: 312-8
276. Postlind H, Danielson A, Lindgren A, et al. Tolterodine, a new muscarinic
receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in
human liver microsomes. Drug Metab Dispos 1998; 26: 289-93
277. Nilvebrant L, Gillberg PG, Sparf B. Antimuscarinic potency and bladder
selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol
Toxicol 1997; 81: 169-72
278. Brynne N, Forslund C, Hallen B, et al. Ketoconazole inhibits the metabolism
of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Phar-
macol 1999; 48: 564-72
279. Brynne N, Dalen P, Alvan G, et al. Influence of CYP2D6 polymorphism on
the pharmacokinetics and pharmacodynamic of tolterodine. Clin Pharmacol
Ther 1998; 63: 529-39
280. Brynne N, Bottiger Y, Hallen B, et al. Tolterodine does not affect the human
in vivo metabolism of the probe drugs caffeine, debrisoquine and omepra-
zole. Br J Clin Pharmacol 1999; 47: 145-50
281. Brynne N, Svanstrom C, Aberg-Wistedt A, et al. Fluoxetine inhibits the
metabolism of tolterodine-pharmacokinetic implications and proposed
clinical relevance. Br J Clin Pharmacol 1999; 48: 553-63
282. Olsson B, Szamosi J. Food does not influence the pharmacokinetics of a new
extended release formulation of tolterodine for once daily treatment of pa-
tients with overactive bladder. Clin Pharmacokinet 2001; 40: 135-43
283. Olsson B, Szamosi J. Multiple dose pharmacokinetics of a new once daily
extended release tolterodine formulation versus immediate release tolter-
odine. Clin Pharmacokinet 2001; 40: 227-35
284. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med
2008; 358: 2482-94
285. Schwartzberg LS. Chemotherapy-induced nausea and vomiting: which an-
tiemetic for which therapy? Oncology (Williston Park) 2007; 21: 946-53;
discussion 954, 959, 962 passim
286. Aapro M. 5-HT3-receptor antagonists in the management of nausea and
vomiting in cancer and cancer treatment. Oncology 2005; 69: 97-109
287. Aapro M, Blower P. 5-Hydroxytryptamine type-3 receptor antagonists for
chemotherapy-induced and radiotherapy-induced nausea and emesis: canwe
safely reduce the dose of administered agents? Cancer 2005; 104: 1-18
288. Evangelista S. Eziopitant: Pfizer. Curr Opin Investig Drugs 2001; 2: 1441-3
289. Fischer V, Baldeck JP, Tse FL. Pharmacokinetics and metabolism of the
5-hydroxytryptamine antagonist tropisetron after single oral doses in hu-
mans. Drug Metab Dispos 1992; 20: 603-7
290. Kutz K. Pharmacology, toxicology and human pharmacokinetics of tropi-
setron. Ann Oncol 1993; 4 Suppl. 3: 15-18
291. Fischer V, Vickers AE, Heitz F, et al. The polymorphic cytochrome P-4502D6
is involved in the metabolism of both 5-hydroxytryptamine antagonists,
tropisetron and ondansetron. Drug Metab Dispos 1994; 22: 269-74
292. Sanwald P, David M, Dow J. Characterization of the cytochrome P450 en-
zymes involved in the in vitro metabolism of dolasetron: comparison with
other indole-containing 5-HT3 antagonists. Drug Metab Dispos 1996; 24:
602-9
293. Obach RS. Cytochrome P450-catalyzed metabolism of ezlopitant alkene
(CJ-12,458), a pharmacologically active metabolite of ezlopitant: enzyme
kinetics and mechanism of an alkene hydration reaction. Drug Metab Dis-
pos 2001; 29: 1057-67
294. Desta Z, Wu GM, Morocho AM, et al. The gastroprokinetic and antiemetic
drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6.
Drug Metab Dispos 2002; 30: 336-43
295. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of
chemotherapy-induced nausea and vomiting: a comparison of their phar-
macology and clinical efficacy. Drugs 1998; 55: 173-89
296. Obach RS. Metabolism of ezlopitant, a nonpeptidic substance P receptor
antagonist, in liver microsomes: enzyme kinetics, cytochrome P450 isoform
identity, and in vitro-in vivo correlation. Drug Metab Dispos 2000; 28:
1069-76
297. Sanchez RI,Wang RW,Newton DJ, et al. Cytochrome P450 3A4 is the major
enzyme involved in the metabolism of the substance P receptor antagonist
aprepitant. Drug Metab Dispos 2004; 32: 1287-92
298. Balfour JA, Goa KL. Dolasetron: a review of its pharmacology and ther-
apeutic potential in the management of nausea and vomiting induced by
chemotherapy, radiotherapy or surgery. Drugs 1997; 54: 273-98
299. Reith MK, Sproles GD, Cheng LK. Human metabolism of dolasetron me-
sylate, a 5-HT3 receptor antagonist. Drug Metab Dispos 1995; 23: 806-12
300. Janicki PK, Schuler HG, Jarzembowski TM, et al. Prevention of post-
operative nausea and vomiting with granisetron and dolasetron in relation to
CYP2D6 genotype. Anesth Analg 2006; 102: 1127-33
301. Milne RJ, Heel RC. Ondansetron: therapeutic use as an antiemetic. Drugs
1991; 41: 574-95
302. Ashforth EI, Palmer JL, Bye A, et al. The pharmacokinetics of ondansetron
after intravenous injection in healthy volunteers phenotyped as poor or ex-
tensive metabolisers of debrisoquine. Br J Clin Pharmacol 1994; 37: 389-91
303. Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmaco-
genomics on postoperative nausea and vomiting: do CYP2D6 allele copy
number and polymorphisms affect the success or failure of ondansetron
prophylaxis? Anesthesiology 2005; 102: 543-9
304. Simpson K, Spencer CM, McClellan KJ. Tropisetron: an update of its use in
the prevention of chemotherapy-induced nausea and vomiting. Drugs 2000;
59: 1297-315
305. Lee CR, Plosker GL, McTavish D. Tropisetron: a review of its pharmaco-
dynamic and pharmacokinetic properties, and therapeutic potential as an
antiemetic. Drugs 1993; 46: 925-43
306. Firkusny L, Kroemer HK, Eichelbaum M. In vitro characterization of cyto-
chrome P450 catalysed metabolism of the antiemetic tropisetron. Biochem
Pharmacol 1995; 49: 1777-84
307. Kim MK, Cho JY, Lim HS, et al. Effect of the CYP2D6 genotype on the
pharmacokinetics of tropisetron in healthy Korean subjects. Eur J Clin
Pharmacol 2003; 59: 111-6
308. Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with
5-hydroxytryptamine type 3 receptor antagonists according to cytochrome
P-450 2D6 genotypes. J Clin Oncol 2002; 20: 2805-11
309. Oppenheimer JJ, Casale TB. Next generation antihistamines: therapeutic
rationale, accomplishments and advances. Expert Opin Investig Drugs 2002;
11: 807-17
310. Devillier P, Roche N, Faisy C. Clinical pharmacokinetics and pharmacody-
namics of desloratadine, fexofenadine and levocetirizine: a comparative
review. Clin Pharmacokinet 2008; 47: 217-30
311. Yumibe N, Huie K, Chen KJ, et al. Identification of human liver cytochrome
P450 enzymes that metabolize the nonsedating antihistamine loratadine:
formation of descarboethoxyloratadine by CYP3A4 andCYP2D6. Biochem
Pharmacol 1996; 51: 165-72
312. Yumibe N, Huie K, Chen KJ, et al. Identification of human liver cytochrome
P450s involved in the microsomal metabolism of the antihistaminic drug
loratadine. Int Arch Allergy Immunol 1995; 107: 420
313. Nakamura K, Yokoi T, Inoue K, et al. CYP2D6 is the principal cytochrome
P450 responsible for metabolism of the histamine H1 antagonist pro-
methazine in human liver microsomes. Pharmacogenetics 1996; 6: 449-57
314. Matsumoto S, Yamazoe Y. Involvement of multiple human cytochromes
P450 in the liver microsomal metabolism of astemizole and a comparison
with terfenadine. Br J Clin Pharmacol 2001; 51: 133-42
315. Nakamura K, Yokoi T, Kodama T, et al. Oxidation of histamine H1 an-
tagonist mequitazine is catalyzed by cytochrome P450 2D6 in human liver
microsomes. J Pharmacol Exp Ther 1998; 284: 437-42
800 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
316. Jones BC, Hyland R, Ackland M, et al. Interaction of terfenadine and its
primary metabolites with cytochrome P450 2D6. Drug Metab Dispos 1998;
26: 875-82
317. Imai T, Taketani M, Suzu T, et al. In vitro identification of the human cyto-
chrome P-450 enzymes involved in the N-demethylation of azelastine. Drug
Metab Dispos 1999; 27: 942-6
318. Nakajima M, Nakamura S, Tokudome S, et al. Azelastine N-demethylation
by cytochrome P-450 (CYP)3A4, CYP2D6, and CYP1A2 in human liver
microsomes: evaluation of approach to predict the contribution of multiple
CYPs. Drug Metab Dispos 1999; 27: 1381-91
319. Goto A, Ueda K, Inaba A, et al. Identification of human P450 isoforms
involved in the metabolism of the antiallergic drug, oxatomide, and its ki-
netic parameters and inhibition constants. Biol Pharm Bull 2005; 28: 328-34
320. Goto A, Adachi Y, Inaba A, et al. Identification of human P450 isoforms
involved in the metabolism of the antiallergic drug, oxatomide, and its in-
hibitory effect on enzyme activity. Biol Pharm Bull 2004; 27: 684-90
321. Kishimoto W, Hiroi T, Sakai K, et al. Metabolism of epinastine, a histamine
H1 receptor antagonist, in human liver microsomes in comparison with that
of terfenadine. Res Commun Mol Pathol Pharmacol 1997; 98: 273-92
322. Narimatsu S, Kariya S, Isozaki S, et al. Involvement of CYP2D6 in oxidative
metabolism of cinnarizine and flunarizine in human liver microsomes.
Biochem Biophys Res Commun 1993; 193: 1262-8
323. Kariya S, Isozaki S, Uchino K, et al. Oxidative metabolism of flunarizine and
cinnarizine by microsomes from B-lymphoblastoid cell lines expressing hu-
man cytochrome P450 enzymes. Biol Pharm Bull 1996; 19: 1511-4
324. Akutsu T, Kobayashi K, Sakurada K, et al. Identification of human cyto-
chrome P450 isozymes involved in diphenhydramine N-demethylation.
Drug Metab Dispos 2007; 35: 72-8
325. He N, Zhang WQ, Shockley D, et al. Inhibitory effects of H1-antihistamines
on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human
liver microsomes. Eur J Clin Pharmacol 2002; 57: 847-51
326. Yasuda SU, Zannikos P, Young AE, et al. The roles of CYP2D6 and ste-
reoselectivity in the clinical pharmacokinetics of chlorpheniramine. Br J Clin
Pharmacol 2002; 53: 519-25
327. Tran VT, Chang RS, Snyder SH. Histamine H1. receptors identified in
mammalian brain membranes with [3H]mepyramine. Proc Natl Acad Sci
U S A 1978; 75: 6290-4
328. Peets EA, Jackson M, Symchowicz S. Metabolism of chlorpheniramine
maleate in man. J Pharmacol Exp Ther 1972; 180: 364-74
329. Yasuda SU, Wellstein A, Likhari P, et al. Chlorpheniramine plasma con-
centration and histamine H1-receptor occupancy. Clin Pharmacol Ther
1995; 58: 210-20
330. Banerji A, Long AA, Camargo CA, et al. Diphenhydramine versus non-
sedating antihistamines for acute allergic reactions: a literature review.
Allergy Asthma Proc 2007; 28: 418-26
331. McGeer PL, Boulding JE, Gibson WC, et al. Drug-induced extrapyramidal
reactions: treatment with diphenhydramine hydrochloride and dihydrox-
yphenylalanine. JAMA 1961; 177: 665-70
332. Chang T, Okerholm RA, Glazko AJ. Identification of diphenydramine
(Benadryl) metabolities in human subjects. Res Commun Chem Pathol
Pharmacol 1974; 9: 391-404
333. Blyden GT, Greenblatt DJ, Scavone JM, et al. Pharmacokinetics of di-
phenhydramine and a demethylated metabolite following intravenous and
oral administration. J Clin Pharmacol 1986; 26: 529-33
334. Sharma A, Hamelin BA. Classic histamine H1 receptor antagonists: a critical
review of their metabolic and pharmacokinetic fate from a bird’s eye view.
Curr Drug Metab 2003; 4: 105-29
335. Breyer-Pfaff U, Fischer D, Winne D. Biphasic kinetics of quaternary am-
monium glucuronide formation from amitriptyline and diphenhydramine in
human liver microsomes. Drug Metab Dispos 1997; 25: 340-5
336. Fischer D, Breyer-Pfaff U. Variability of diphenhydramine N-glucuronida-
tion in healthy subjects. Eur J Drug Metab Pharmacokinet 1997; 22: 151-4
337. Luo H, Hawes EM, McKay G, et al. N+-glucuronidation of aliphatic tertiary
amines, a general phenomenon in the metabolism of H1-antihistamines in
humans. Xenobiotica 1991; 21: 1281-8
338. Lessard E, Yessine MA, Hamelin BA, et al. Diphenhydramine alters the
disposition of venlafaxine through inhibition of CYP2D6 activity in humans.
J Clin Psychopharmacol 2001; 21: 175-84
339. Haria M, Fitton A, Peters DH. Loratadine: a reappraisal of its pharmaco-
logical properties and therapeutic use in allergic disorders. Drugs 1994; 48:
617-37
340. Ramanathan R, Reyderman L, Su AD, et al. Disposition of desloratadine in
healthy volunteers. Xenobiotica 2007; 37: 770-87
341. RamanathanR,Reyderman L,Kulmatycki K, et al. Disposition of loratadine
in healthy volunteers. Xenobiotica 2007; 37: 753-69
342. Yin OQ, Shi XJ, Tomlinson B, et al. Effect of CYP2D6*10 allele on the
pharmacokinetics of loratadine in Chinese subjects. Drug Metab Dispos
2005; 33: 1283-7
343. Saruwatari J, Matsunaga M, Ikeda K, et al. Impact of CYP2D6*10 on
H1-antihistamine-induced hypersomnia. Eur J Clin Pharmacol 2006; 62:
995-1001
344. Lotsch J. Opioid metabolites. J Pain Symptom Manage 2005; 29: S10-24
345. Dayer P, Desmeules J, Leemann T, et al. Bioactivation of the narcotic drug
codeine in human liver is mediated by the polymorphic monooxygenase
catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI).Biochem Biophys Res Commun 1988; 152: 411-6
346. Yue QY, Sawe J. Different effects of inhibitors on the O- and N-demethyla-
tion of codeine in human liver microsomes. Eur J Clin Pharmacol 1997; 52:
41-7
347. Ohno S, Kawana K, Nakajin S. Contribution of UDP-glucuronosyl-
transferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic
properties. Drug Metab Dispos 2008; 36: 688-94
348. Lotsch J, SkarkeC, Liefhold J, et al. Genetic predictors of the clinical response
to opioid analgesics: clinical utility and future perspectives. Clin Pharma-
cokinet 2004; 43: 983-1013
349. Eckhardt K, Li S, Ammon S, et al. Same incidence of adverse drug events after
codeine administration irrespective of the genetically determined differences
in morphine formation. Pain 1998; 76: 27-33
350. Poulsen L, Brosen K, Arendt-Nielsen L, et al. Codeine and morphine in
extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic
effect and side effects. Eur J Clin Pharmacol 1996; 51: 289-95
351. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects
of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996;
278: 1165-74
352. Tyndale RF, Droll KP, Sellers EM. Genetically deficient CYP2D6 metabo-
lism provides protection against oral opiate dependence. Pharmacogenetics
1997; 7: 375-9
353. Mikus G, Bochner F, Eichelbaum M, et al. Endogenous codeine and mor-
phine in poor and extensive metabolisers of the CYP2D6 (debrisoqui-
ne/sparteine) polymorphism. J Pharmacol Exp Ther 1994; 268: 546-51
354. Mikus G, Morike K, Griese EU, et al. Relevance of deficient CYP2D6 in
opiate dependence. Pharmacogenetics 1998; 8: 565-8
355. Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin
Pharmacol Ther 2007; 81: 429-44
356. Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine poi-
soning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;
368: 704
357. Madadi P, Ross CJ, Hayden MR, et al. Pharmacogenetics of neonatal opioid
toxicity following maternal use of codeine during breastfeeding: a case-
control study. Clin Pharmacol Ther 2009; 85: 31-5
Pharmacogenetics of CYP2D6 801
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
358. Edwards JE, McQuay HJ, Moore RA. Single dose dihydrocodeine for acute
postoperative pain. Cochrane Database Syst Rev 2000; (4): CD002760
359. Kirkwood LC, Nation RL, Somogyi AA. Characterization of the human
cytochrome P450 enzymes involved in the metabolism of dihydrocodeine.
Br J Clin Pharmacol 1997; 44: 549-55
360. Fromm MF, Hofmann U, Griese EU, et al. Dihydrocodeine: a new opioid
substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther
1995; 58: 374-82
361. Wilder-Smith CH, Hufschmid E, Thormann W. The visceral and somatic
antinociceptive effects of dihydrocodeine and its metabolite, dihy-
dromorphine: a cross-over study with extensive and quinidine-induced poor
metabolizers. Br J Clin Pharmacol 1998; 45: 575-81
362. Schmidt H, Vormfelde SV, Walchner-Bonjean M, et al. The role of active
metabolites in dihydrocodeine effects. Int J Clin Pharmacol Ther 2003; 41:
95-106
363. Chen ZR, Irvine RJ, Somogyi AA, et al. Mu receptor binding of some com-
monly used opioids and their metabolites. Life Sci 1991; 48: 2165-71
364. Hutchinson MR, Menelaou A, Foster DJ, et al. CYP2D6 and CYP3A4 in-
volvement in the primary oxidative metabolism of hydrocodone by human
liver microsomes. Br J Clin Pharmacol 2004; 57: 287-97
365. Otton SV, Schadel M, Cheung SW, et al. CYP2D6 phenotype determines the
metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol
Ther 1993; 54: 463-72
366. Lelas S, Wegert S, Otton SV, et al. Inhibitors of cytochrome P450 differen-
tially modify discriminative-stimulus and antinociceptive effects of hydro-
codone and hydromorphone in rhesus monkeys. Drug Alcohol Depend
1999; 54: 239-49
367. Kaplan HL, Busto UE, Baylon GJ, et al. Inhibition of cytochrome P450 2D6
metabolism of hydrocodone to hydromorphone does not importantly affect
abuse liability. J Pharmacol Exp Ther 1997; 281: 103-8
368. Poyhia R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmaco-
kinetics and pharmacodynamics. J Pain Symptom Manage 1993; 8: 63-7
369. Leow KP, Smith MT, Williams B, et al. Single-dose and steady-state phar-
macokinetics and pharmacodynamics of oxycodone in patients with cancer.
Clin Pharmacol Ther 1992; 52: 487-95
370. Lalovic B, Phillips B, Risler LL, et al. Quantitative contribution of CYP2D6
and CYP3A to oxycodone metabolism in human liver and intestinal mi-
crosomes. Drug Metab Dispos 2004; 32: 447-54
371. Otton SV,WuD, Joffe RT, et al. Inhibition by fluoxetine of cytochrome P450
2D6 activity. Clin Pharmacol Ther 1993; 53: 401-9
372. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the
pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol
Ther 1998; 64: 603-11
373. Garrido MJ, Troconiz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999; 42: 61-6
374. Kristensen K, Christensen CB, Christrup LL. The m1, m2, d, k opioid receptor
binding profiles of methadone stereoisomers and morphine. Life Sci 1995;
56: PL45-50
375. de Vos JW, Geerlings PJ, van den Brink W, et al. Pharmacokinetics of me-
thadone and its primary metabolite in 20 opiate addicts. Eur J Clin Phar-
macol 1995; 48: 361-6
376. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in
the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos
2003; 31: 742-7
377. Coller JK, Joergensen C, Foster DJ, et al. Lack of influence of CYP2D6
genotype on the clearance of (R)-, (S)- and racemic-methadone. Int J Clin
Pharmacol Ther 2007; 45: 410-7
378. Crettol S, Deglon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotypes
and phenotypes: influence on methadone plasma levels and response to
treatment. Clin Pharmacol Ther 2006; 80: 668-81
379. Shiran MR, Chowdry J, Rostami-Hodjegan A, et al. A discordance between
cytochrome P450 2D6 genotype and phenotype in patients undergoing me-
thadone maintenance treatment. Br J Clin Pharmacol 2003; 56: 220-4
380. Wu D, Otton SV, Sproule BA, et al. Inhibition of human cytochrome P450
2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 1993; 35: 30-4
381. Begre S, von Bardeleben U, Ladewig D, et al. Paroxetine increases steady-
state concentrations of (R)-methadone in CYP2D6 extensive but not poor
metabolizers. J Clin Psychopharmacol 2002; 22: 211-5
382. Eap CB, Bertschy G, Powell K, et al. Fluvoxamine and fluoxetine do not
interact in the same way with the metabolism of the enantiomers of metha-
done. J Clin Psychopharmacol 1997; 17: 113-7
383. CobbMN,Desai J, Brown Jr LS, et al. The effect of fluconazole on the clinical
pharmacokinetics of methadone. Clin Pharmacol Ther 1998; 63: 655-62
384. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmaco-
kinet 2004; 43: 879-923
385. Paar WD, Poche S, Gerloff J, et al. Polymorphic CYP2D6 mediates O-de-
methylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997;
53: 235-9
386. Subrahmanyam V, Renwick AB, Walters DG, et al. Identification of cyto-
chrome P-450 isoforms responsible for cis-tramadol metabolism in human
liver microsomes. Drug Metab Dispos 2001; 29: 1146-55
387. Abdel-Rahman SM, Leeder JS, Wilson JT, et al. Concordance between tra-
madol and dextromethorphan parent/metabolite ratios: the influence of
CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Phar-
macol 2002; 42: 24-9
388. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tra-
madol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636-44
389. Enggaard TP, Poulsen L, Arendt-Nielsen L, et al. The analgesic effect of
tramadol after intravenous injection in healthy volunteers in relation to
CYP2D6. Anesth Analg 2006; 102: 146-50
390. Slanar O, Nobilis M, Kvetina J, et al. Miotic action of tramadol is determined
by CYP2D6 genotype. Physiol Res 2007; 56: 129-36
391. Fliegert F, Kurth B, Gohler K. The effects of tramadol on static and dynamic
pupillometry in healthy subjects: the relationship between pharmacody-
namics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Clin
Pharmacol 2005; 61: 257-66
392. Wang G, Zhang H, He F, et al. Effect of the CYP2D6*10 C188T poly-
morphism on postoperative tramadol analgesia in a Chinese population.
Eur J Clin Pharmacol 2006; 62: 927-31
393. Gan SH, Ismail R, Wan Adnan WA, et al. Population pharmacokinetic
modelling of tramadol with application of the NPEM algorithms. J Clin
Pharm Ther 2004; 29: 455-63
394. Halling J,Weihe P, BrosenK.CYP2D6 polymorphism in relation to tramadol
metabolism: a study of Faroese patients. Ther Drug Monit 2008; 30: 271-5
395. Gan SH, Ismail R, Wan Adnan WA, et al. Impact of CYP2D6 genetic
polymorphism on tramadol pharmacokinetics and pharmacodynamics.
Mol Diagn Ther 2007; 11: 171-81
396. Pedersen RS, Damkier P, BrosenK. Tramadol as a new probe for cytochrome
P450 2D6 phenotyping: a population study. Clin Pharmacol Ther 2005; 77:
458-67
397. Pedersen RS, Damkier P, Brosen K. Enantioselective pharmacokinetics of
tramadol in CYP2D6 extensive and poor metabolizers. Eur J Clin Phar-
macol 2006; 62: 513-21
398. Garcia-Quetglas E, Azanza JR, Sadaba B, et al. Pharmacokinetics of tra-
madol enantiomers and their respective phase I metabolites in relation to
CYP2D6 phenotype. Pharmacol Res 2007; 55: 122-30
399. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on
postoperative tramadol analgesia. Pain 2003; 105: 231-8
802 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
400. Dalen P, Frengell C, Dahl ML, et al. Quick onset of severe abdominal pain
after codeine in an ultrarapidmetabolizer of debrisoquine. Ther DrugMonit
1997; 19: 543-4
401. De Leon J, Dinsmore L, Wedlund P. Adverse drug reactions to oxycodone
and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psycho-
pharmacol 2003; 23: 420-1
402. Kirchheiner J, Keulen JT, Bauer S, et al. Effects of the CYP2D6 gene dupli-
cation on the pharmacokinetics and pharmacodynamics of tramadol. J Clin
Psychopharmacol 2008; 28: 78-83
403. Marchetti P,Giannarelli R, di CarloA, et al. Pharmacokinetic optimisation of
oral hypoglycaemic therapy. Clin Pharmacokinet 1991; 21: 308-17
404. Marchetti P, Navalesi R. Pharmacokinetic-pharmacodynamic relation-
ships of oral hypoglycaemic agents. An update. Clin Pharmacokinet 1989;
16: 100-28
405. Oates NS, Shah RR, Idle JR, et al. Genetic polymorphism of phenformin
4-hydroxylation. Clin Pharmacol Ther 1982; 32: 81-9
406. Shah RR, Evans DA, Oates NS, et al. The genetic control of phenformin
4-hydroxylation. J Med Genet 1985; 22: 361-6
407. Shah RR, Oates NS, Idle JR, et al. Genetic impairment of phenformin me-
tabolism. Lancet 1980; 1: 1147
408. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral
antidiabetic agents. Drug Saf 1994; 11: 223-41
409. Oates NS, Shah RR, Idle JR, et al. Influence of oxidation polymorphism on
phenformin kinetics and dynamics. Clin Pharmacol Ther 1983; 34: 827-34
410. Oates NS, Shah RR, Idle JR, et al. Phenformin-induced lacticacidosis asso-
ciated with impaired debrisoquine hydroxylation. Lancet 1981; 1: 837-8
411. Wiholm BE, Alvan G, Bertilsson L, et al. Hydroxylation of debrisoquine in
patients with lacticacidosis after phenformin. Lancet 1981; 1: 1098-9
412. Sengupta S, Jordan VC. Selective estrogen modulators as an anticancer tool:
mechanisms of efficiency and resistance. Adv Exp Med Biol 2008; 630:
206-19
413. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators-mechan-
isms of action and application to clinical practice. N Engl J Med 2003; 348:
618-29
414. Jordan VC, O’Malley BW. Selective estrogen-receptor modulators and anti-
hormonal resistance in breast cancer. J Clin Oncol 2007; 25: 5815-24
415. Jordan VC. Chemoprevention of breast cancer with selective oestrogen-
receptor modulators. Nat Rev Cancer 2007; 7: 46-53
416. Desta Z, Ward BA, Soukhova NV, et al. Comprehensive evaluation of
tamoxifen sequential biotransformation by the human cytochrome P450
system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp
Ther 2004; 310: 1062-75
417. Beverage JN, Sissung TM, Sion AM, et al. CYP2D6 polymorphisms and the
impact on tamoxifen therapy. J Pharm Sci 2007; 96: 2224-31
418. Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma
concentrations after coadministration of tamoxifen and the selective ser-
otonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003; 95: 1758-64
419. Crewe HK, Notley LM, Wunsch RM, et al. Metabolism of tamoxifen by
recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy,
40-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hy-
droxytamoxifen. Drug Metab Dispos 2002; 30: 869-74
420. Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human
liver. Cancer Res 1997; 57: 3402-6
421. Dehal SS, Kupfer D. Cytochrome P-450 3A and 2D6 catalyze ortho hydro-
xylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene)
yielding tamoxifen catechol: involvement of catechols in covalent binding to
hepatic proteins. Drug Metab Dispos 1999; 27: 681-8
422. Ghobadi C,GregoryA,CreweHK, et al. CYP2D6 is primarily responsible for
the metabolism of clomiphene. Drug Metab Pharmacokinet 2008; 23: 101-5
423. Poon GK, Chui YC, McCague R, et al. Analysis of phase I and phase II
metabolites of tamoxifen in breast cancer patients. DrugMetabDispos 1993;
21: 1119-24
424. Jacolot F, Simon I, Dreano Y, et al. Identification of the cytochrome P450
IIIA family as the enzymes involved in the N-demethylation of tamoxifen in
human liver microsomes. Biochem Pharmacol 1991; 41: 1911-9
425. Katzenellenbogen BS, Norman MJ, Eckert RL, et al. Bioactivities, estrogen
receptor interactions, and plasminogen activator-inducing activities of ta-
moxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer
cells. Cancer Res 1984; 44: 112-9
426. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and
tamoxifen metabolism during adjuvant breast cancer treatment. J Natl
Cancer Inst 2005; 97: 30-9
427. Gjerde J, Hauglid M, Breilid H, et al. Effects of CYP2D6 and SULT1A1
genotypes including SULT1A1 gene copy number on tamoxifenmetabolism.
Ann Oncol 2008; 19: 56-61
428. Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome
with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 geno-
types. J Clin Oncol 2007; 25: 5187-93
429. Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6
metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res
Treat 2007; 101: 113-21
430. Bonanni B, Macis D, Maisonneuve P, et al. Polymorphism in the CYP2D6
tamoxifen-metabolizing gene influences clinical effect but not hot flashes:
data from the Italian Tamoxifen Trial. J Clin Oncol 2006; 24: 3708-9; author
reply 3709
431. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and
inhibitors on tamoxifen metabolism: implication for optimization of breast
cancer treatment. Clin Pharmacol Ther 2006; 80: 61-74
432. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen bio-
transformation is associated with clinical outcomes of efficacy and hot fla-
shes. J Clin Oncol 2005; 23: 9312-8
433. Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and
survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol
2008; 19: 1423-9
434. Kiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recur-
rence-free survival in breast cancer patients receiving adjuvant tamoxifen
therapy. Cancer Sci 2008; 99: 995-9
435. Lim HS, Ju Lee H, Seok Lee K, et al. Clinical implications of CYP2D6
genotypes predictive of tamoxifen pharmacokinetics in metastatic breast
cancer. J Clin Oncol 2007; 25: 3837-45
436. Nowell SA, Ahn J, Rae JM, et al. Association of genetic variation in ta-
moxifen-metabolizing enzymes with overall survival and recurrence of dis-
ease in breast cancer patients. Breast Cancer Res Treat 2005; 91: 249-58
437. Wegman P, Vainikka L, Stal O, et al. Genotype of metabolic enzymes and the
benefit of tamoxifen in postmenopausal breast cancer patients. Breast
Cancer Res 2005; 7: R284-90
438. Wegman P, Elingarami S, Carstensen J, et al. Genetic variants of CYP3A5,
CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in post-
menopausal patients with breast cancer. Breast Cancer Res 2007; 9: R7
439. Kirchheiner J. CYP2D6 phenotype prediction from genotype: which system is
the best? Clin Pharmacol Ther 2008; 83: 225-7
440. Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role
of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther 2008; 83:
160-6
441. Takimoto CH. Can tamoxifen therapy be optimized for patients with breast
cancer on the basis of CYP2D6 activity assessments? Nat Clin Pract Oncol
2007; 4: 152-3
442. Wennerholm A, Dandara C, Sayi J, et al. The African-specific CYP2D617
allele encodes an enzyme with changed substrate specificity. Clin Pharmacol
Ther 2002; 71: 77-88
Pharmacogenetics of CYP2D6 803
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)
443. Griese EU, Zanger UM, Brudermanns U, et al. Assessment of the predictive
power of genotypes for the in-vivo catalytic function of CYP2D6 in a
German population. Pharmacogenetics 1998; 8: 15-26
444. Steimer W, Zopf K, von Amelunxen S, et al. Allele-specific change of con-
centration and functional gene dose for the prediction of steady-state serum
concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6
extensive and intermediate metabolizers. Clin Chem 2004; 50: 1623-33
445. Hinrichs JW, LooversHM, Scholten B, et al. Semi-quantitativeCYP2D6 gene
doses in relation to metabolic ratios of psychotropics. Eur J Clin Pharmacol
2008; 64: 979-86
446. Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 activity score: trans-
lating genotype information into a qualitative measure of phenotype. Clin
Pharmacol Ther 2008; 83: 234-42
447. Gaedigk A, Bradford LD, Alander SW, et al.CYP2D6*36 gene arrangements
within theCYP2D6 locus: association ofCYP2D6*36 with poormetabolizer
status. Drug Metab Dispos 2006; 34: 563-9
448. Gaedigk A, Bradford LD, Marcucci KA, et al. Unique CYP2D6 activity
distribution and genotype-phenotype discordance in Black Americans. Clin
Pharmacol Ther 2002; 72: 76-89
449. Gaedigk A, Ndjountche L, Gaedigk R, et al. Discovery of a novel nonfunc-
tional cytochrome P450 2D6 allele, CYP2D6*42, in African American
subjects. Clin Pharmacol Ther 2003; 73: 575-6
450. Yamazaki H, Kiyotani K, Tsubuko S, et al. Two novel haplotypes of
CYP2D6 gene in a Japanese population. Drug Metab Pharmacokinet 2003;
18: 269-71
451. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450
enzymes and its clinical impact. Drug Metab Rev 2009; 41: 89-295
452. Rowland P, Blaney FE, Smyth MG, et al. Crystal structure of human cyto-
chrome P450 2D6. J Biol Chem 2006; 281: 7614-22
453. Zhou SF, Liu JP, Lai XS. Substrate specificity, inhibitors and regulation of
human cytochrome P450 2D6 and implications in drug development. Curr
Med Chem 2009; 16: 2661-805
454. Paine MJ, McLaughlin LA, Flanagan JU, et al. Residues glutamate 216
and aspartate 301 are key determinants of substrate specificity and product
regioselectivity in cytochrome P450 2D6. J Biol Chem 2003; 278: 4021-7
455. Mackman R, Tschirret-Guth RA, Smith G, et al. Active-site topologies of
humanCYP2D6 and its aspartate-301- glutamate, asparagine, and glycine
mutants. Arch Biochem Biophys 1996; 331: 134-40
Correspondence: Associate Professor Shu-Feng Zhou, Discipline of Chinese
Medicine, School of Health Sciences, RMIT University, Plenty Road,
Bundoora, VIC 3083, Australia.
E-mail: shufeng.zhou@rmit.edu.au
804 Zhou
ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (12)