Zhou 2009 Part 2

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

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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


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



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

766 Zhou


(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)



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



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

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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]



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


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-



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


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.



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


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



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 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.



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



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]

782 Zhou


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


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-



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

784 Zhou


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


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-



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-

786 Zhou


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



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

788 Zhou


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.



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


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


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.



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


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.

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Correspondence: Associate Professor Shu-Feng Zhou, Discipline of Chinese

Medicine, School of Health Sciences, RMIT University, Plenty Road,

Bundoora, VIC 3083, Australia.

E-mail: [email protected]

804 Zhou


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