Clinical Pharmacokinetics of Fluoxetine

Clin. Pharmacokinet. 26 (3): 201-214,1994 0312-5963/94/0003-0201/$07.00/0 Adis International Limited. All rights reversed

Clinical Pharmacokinetics of Fluoxetine

Alfredo C. Altamura,1 Anna R. Moro2 and Mauro Percudani3 1 Department of Psychiatry, University of Cagliari, Cagliari, Italy 2 Department of Psychiatry, University of Milan, Milan, Italy 3 Department of Psychiatry, General Hospital of Magenta, Milan, Italy

Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume of distribution. The elimination half-life of fluoxetine is about 1 to 4 days, while that of its metabolite norfluoxetine ranges from 7 to 15 days.

Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction).

In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine (compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by either obesity or renal impairment.

On the basis of results of plasma concentration-clinical response relationship studies, there appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus norfluoxetine above 500 µg/L appear to be associated with a poorer clinical response than lower concentrations.

Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine in -creased the blood concentrations of antipsychotics or antidepressants. The interactions between fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially serious, and can lead to the 'serotonergic syndrome'. This is because of synergistic pharmacody-namic effects and the influence of fluoxetine on the bioavailability of these compounds.

DRUG DISPOSITION

201 202 203 204 204 205 205 207 207 207 207 208 208 209 211

1. Analytical Methods 2. Absorption and Bioavailability 3. Distribution

3.1. Distribution in the Brain 4. Metabolism and Elimination 5. Nonlinear Pharmacokinetic Profile

5.1. Polymorphic Metabolism 6. Pharmacokinetics in Special Populations

6.1. Elderly Patients 6.2. Patients with Renal Impairment 6.3. Patients with Hepatic Dysfunction 6.4. Obese Patients

7. Concentration-Response Studies 8. Drug Interactions 9. Conclusions

Contents

Summary

202 Clin. Pharmacokinet. 26 (3) 1994

The selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are a relatively novel class of compounds with antidepressant properties. They are structurally heterogeneous, but share similar actions on 5-HT brain pathways, because they increase the availability of this neu-rotransmitter at cerebral receptor sites. Fluoxetine is a bicyclic derivative of phenylpropylamine. It is the most widely used SSRI, and is prescribed for a variety of psychopathological conditions including mood and eating disorders, obsessive-compulsive disorders, depression in the elderly and dysthymia (Altamura & Mauri 1991; Altamura et al. 1989; Benfield et al. 1986; Rosenthal et al. 1992). Other SSRIs include paroxetine, sertraline, fluvoxamine and citalopram. For an overview of the pharmaco-kinetics of these agents readers are referred to a review recently published in the Journal (van Harten 1993).

Down regulation of 5-HT1 receptors is the most commonly reported central nervous system (CNS) effect of subchronic exposure (i.e. for at least 10 days) of intact animal models to fluoxetine. The 5-HT1 receptors were evaluated in 15 experiments. It was found that the number of receptors was re-duced, without a change in receptor affinity for its ligand (reviewed by Beasley et al. 1992).

More controversial is the activity of fluoxetine on 5-HT1 receptors. In fact, down regulation, up regulation and no effect on receptors have all been reported (Baron 1988; Dumbrille-Ross & Tang 1983; Wamsley et al. 1987). Fluoxetine seems to facilitate serotonergic transmission via down regulation of presynaptic inhibitory au-toreceptors (Beasley et al. 1992), with no effect on muscarinic receptors and doubtful effects on β-adrenergic receptors (Byerley et al. 1988). Ini-tially, it was suggested that the effective dose of fluoxetine was at least 80 mg/day, but more re-cently a dosage of 20 mg/day has been shown to have a better benefit-to-risk ratio (Altamura et al. 1988). Indeed, in the elderly, we have found ad-ministration of fluoxetine 20mg 3 times weekly to be clinically effective.

The pharmacokinetic profile of fluoxetine is dif-

ferent from that of other drugs of its class. For ex-ample, it has a longer half-life, active metabolites and non-linear pharmacokinetics. Knowledge of the differences allows improved clinical manage-ment during administration of fluoxetine. More-over, fluoxetine plasma concentration-effect data seem useful in the rationalisation of therapy in de-pressed patients (Altamura & Montgomery 1990). This article reviews the pharmacokinetic profile of fluoxetine, emphasising the relevance of phar-macokinetics to the appropriate clinical use of the drug.

1. Analytical Methods

High performance liquid chromatography (HPLC) with ultraviolet or fluorescence detection and gas chromatography with electron capture (GC-EC) detection are most commonly used to de-termine serum concentrations of fluoxetine and its metabolites (Kelly et al. 1989; Nichols et al. 1992; Orsulak et al. 1988; Suckow et al. 1992b). Flame ionisation or nitrogen selective detection (Roeth-ger 1990; Rohrig & Prouty 1989) have also been used, but these methods are helpful only when fluoxetine is present at potentially toxic concentra-tions.

A simple HPLC procedure allows fluoxetine or norfluoxetine (formed by N-demethylation) 20 µg/L to be detected in a sample of only 0.5ml (data on file, Eli Lilly). This procedure is, therefore, par-ticularly suitable for clinical application. Suckow et al. (1992b) determined the plasma concentration of fluoxetine and norfluoxetine using HPLC with fluorescence detection. The highly fluorescent de-rivatives were separated in a reversed-phase C18 column with a mobile phase of phosphate buffer and acetonitrile. Dansylated fluoxetine, nor-fluoxetine and internal standard were eluted in less than 14 minutes, and there was no interference from endogenous material. Assay variability was confirmed via comparison of these results with those obtained by the use of a liquid chromato-graphic method with ultraviolet detection for sam-ples from 110 patients (r = 0.993 for fluoxetine, r = 0.957 for norfluoxetine). Furthermore, the iden-

Pharmacokinetics of Fluoxetine 203

tity of the dansylated derivatives was verified by positive chemical ionisation mass spectroscopy. The lower limit of detection was about 3 µg/L. No major antidepressant, or antipsychotic drug, or me-tabolite of these drugs, interfered with the quanti-fication of plasma fluoxetine and norfluoxetine Concentrations. Determination of fluoxetine and norfluoxetine using GC-EC was originally described by Nash et al. (1982). However, a more rapid, selective and sensitive method, using a solid-phase extraction column, has since been described (Dixit et al. (1991). Linear quantitative response curves for fluoxetine and norfluoxetine were generated over a concentration range of 20 to 200 g/L. However, HPLC remains the most widely used analytical method and, in our opinion, it appears to allow more selective and sensitive determination of fluoxetine and its metabolite.

2. Absorption and Bioavailability Fluoxetine is well absorbed from the gastroin-

tetinal tract after oral administration, and its bio-availability is not affected by the presence of food (Bergstrom etal. 1984). Absolute bioavailability of oral fluoxetine in dogs is about 72% of the intrave-nous dose (Bergstrom et al. 1986b).

Following the oral administration of [14C]fluoxetine to humans, the plasma concentra-tions of fluoxetine, its N-demethylated metabolite norfluoxetine), and total radioactivity were maxi-mal within 4 to 8 hours postdose, and then declined over a long period (Bergstrom et al. 1988). In a metabolism study undertaken at steady-state, a 50/50 mixture of unlabelled fluoxetine and deute-rium-labelled fluoxetine (fluoxetine with 5 of the hydrogens replaced by deuterium) was given to volunteers at a dosage of 60mg daily over a period of 45 days (Farid et al. 1986). Steady-state plasma fluoxetine concentrations were achieved by about day 30. On the following day (day 31), a radiolabelled dose of [14C]fluoxetine was adminis-tered to the volunteers, and the disposition and me-labolism of this radiolabelled dose was deter-mined. Approximately 75% of the administered

I4C-radioactivity was excreted in the urine over a subsequent 30-day period, and 10% of the dose was recovered in the faeces over a 20-day period. Extrapolation of the excretion profile in urine and faeces to infinite time indicated that approximately 80% of the radioactivity was excreted in urine and 15% of the dose was excreted in faeces. Thus, mass balance accounted for a total excretion of about 95% of the administered 14C-dose.

The pharmacokinetic profile of fluoxetine after administration of a single oral dose has been estab-lished (table I). After a single dose, peak plasma fluoxetine concentrations (Cmax) in humans occurred between 6 and 8 hours postdose, regardless of whether the drug was administered as a capsule or as a solutipn (Lemberger et al. 1985). Maximal CNS efficacy, assessed by electroencephalogram monitoring, occurred between 8 and 10 hours postdose. The time lag between Cmax and maximal pharmacodynamic effects may be due, in part, to a delay in the formation of the active metabolite (Saletu & Grunberger 1985).

The mean time taken to achieve Cmax values (tmax) was delayed by 3 to 5 hours when fluoxetine was administered with food. However, the extent of absorption and the Cmax values were virtually unchanged by food (Lemberger et al. 1985).

Over an oral dose range of 20 to 80mg, Cmax values were dose-proportional (Lemberger et al. 1985). However, because fluoxetine (in common with other SSRIs) undergoes extensive first-pass metabolism in the liver, marked interindividual


Fig. 1. Plasma versus brain fluoxetine plus norfluoxetine concen-trations in 8 patients who received different dosages of fluoxetine (from Renshaw et al. 1992, with permission).

differences in Cmax values are apparent after standard daily dosages. For example, a 3- to 4-fold in-terindividual variation in Cmax (15 to 55 µg/L) was observed after administration of a single dose of fluoxetine 40mg to 25 healthy volunteers [Aronoff etal. 1984].

During long term administration steady-state plasma fluoxetine concentrations were achieved within 2 to 4 weeks (Bergstrom et al. 1986a). Fur-thermore, no accumulation occurred after adminis-tration of the drug for up to 3 years.

3. Distribution

Fluoxetine and norfluoxetine each have a vol-ume of distribution (Vd) of 20 to 42 L/kg. This large Vd is the result of high plasma protein binding (>95%) and extensive tissue distribution. The ratio of fluoxetine to norfluoxetine concentrations were similar in the cerebral cortex, striatum, hip-pocampus, hypothalamus, brain stem and cerebel-lum of rat brains 1 hour after a single dose (re-viewed in Benfield et al. 1986).

Long term administration of fluoxetine to rats and dogs led to highest concentrations of the drug in the lungs (rats) and liver (dogs) [reviewed in Benfield et al. 1986]. Moreover, in humans, plasma concentrations of fluoxetine and norfluoxetine were similar in obese and lean individuals when

fluoxetine 60mg was administered to both (data on file, Eli Lilly). Therefore, it would appear that the drug distributes to a small degree only in adipose tissue, as suggested by the findings in obese pa-tients.

3.1 Distribution in the Brain

In vivo, 19fluorine nuclear magnetic resonance spectroscopy was used to measure the brain con-centration of fluoxetine and norfluoxetine in 5 pa-tients with obsessive-compulsive disorder and 3 patients with major depression (Rensbaw et al. 1992). All patients had been taking fluoxetine 60 to 100 mg/day for a minimum of 3 months (mean of 13 ± 6 months). No patient had their dosage changed in the 4 weeks prior to initiation of the study. Fluoxetine and norfluoxetine brain concen-trations were significantly higher (2.6 times) than their corresponding plasma concentrations. The daily dosage correlated with calculated brain con-centrations more closely than did plasma concen-tration (fig. 1). However, the poor correlation be-tween plasma and brain concentrations (r = 0.58, d.f = 7) was disproportionately affected by values obtained from 1 of the 8 patients whose brain con-centration of fluoxetine plus norfluoxetine was 4.9 times higher than the corresponding plasma con-centration. When data from this patient were ex-cluded from the analysis, the correlation coeffi-cient between plasma and brain concentrations improved (r = 0.82; d.f = 7). Although there were some limitations to this study (e.g. inactive fluo-rine-containing metabolites of fluoxetine would have been detected by this technique), these results were consistent with data derived from animal ex-periments.

4. Metabolism and Elimination

The main metabolite of fluoxetine is norfluoxet-ine. Norfluoxetine has similar potency and selec-tivity of 5-HT uptake inhibition compared with the parent compound (Fuller & Wong 1987). There-fore, knowledge of its pharmacokinetic profile is relevant because the metabolite can influence the clinical efficacy of fluoxetine.


The urinary elimination of metabolites of fluoxetine has been studied under steady-state con-ditions in normal volunteers. In one study, volun-teers received a single oral 60mg dose of 14C-labelled drug on the thirty-ninth day of administration of 60 mg/day for 45 days (Farid et al. 1986). Approximately 75% of the I4C-radioac-tivity was excreted in the urine during the 30 days postdose, and 10% was recovered in the faeces dur-ing the 20 days postdose. By extrapolation of the excretion profile to infinite time, it was shown that approximately 80% of the administered dose would be eliminated in the urine and 15% of the dose in the faeces (see section 2). Moreover, stud-ies have revealed that about 11% of the adminis-tered dose was excreted as fluoxetine, 7% was ex-creted as norfluoxetine, and 7 and 8% were fluoxetine and norfluoxetine glucuronides, respec-tively. Finally, more than 20% of the radioactivity was excreted in urine as hippuric acid, a glycine Conjugate of benzoic acid (Bergstrom et al. 1988).

After administration of a single 30mg oral dose of radiolabelled fluoxetine to 3 volunteers, 60% of the dose was recovered in urine and 16% of the dose was recovered in the faeces after 35 and 28 days postdose, respectively. Only 2 to 5% of the drug excreted in the urine was unchanged, suggesting that fluoxetine undergoes extensive hepatic metabolism (Lemberger et al. 1985). A proposed schema for fluoxetine metabolism is shown in figure 2.

Fluoxetine has an elimination half-life (t½β) of about 1 to 4 days, whereas the t½β of norfluoxetine ranged from 7 to 15 days. Steady-state plasma con-centrations of both fluoxetine and its major meta-bolite were achieved within about 4 weeks when fluoxetine was administered daily. Some accumu-lation of the drug appears to occur in the first 4 weeks of therapy before steady-state concentra-tions are achieved, e.g. areas under the plasma con-centration-time curve (AUC) were larger after multiple-dose administration than those observed after single-dose administration of the same dose (data on file, Eli Lilly). This seems to be due to changes in t½β (1.9 vs 5.7 days) and clearance (CL)

[35.5 vs 10.8 L/h] after administration of a single dose compared with multiple doses (Bergstrom et al. 1985). However, after achievement of steady-state no further accumulation occurs (see section 2).

5. Nonlinear Pharmacokinetic Profile

The pharmacokinetics of fluoxetine was shown to be non-linear in both healthy volunteers and pa-tients with depression. Higher dosages of fluox-etine resulted in disproportionately higher plasma concentrations (Bergstrom et al. 1986a; Sommi et al. 1987). A comparison of single-dose versus steady-state pharmacokinetics in men (Bergstrom et al. 1985) showed that the t½β was longer (5.7 vs 1.9 days) and CL was lower (10.8 vs 35.5 L/h) after multiple-dose administration than after single-dose administration. This change in pharmacoki-netics leads to a larger AUC at steady-state than is observed after a single dose. The non-linear nature of the pharmacokinetics of fluoxetine was also shown in a steady-state study in patients with de-pression (Bergstrom et al. 1986b). Steady-state concentrations of fluoxetine and norfluoxetine in these depressed patients, who had been treated with fluoxetine for more than 1 year, were similar to the steady-state concentrations observed in vol-unteers and patients who had been given fluoxetine for 4 to 6 weeks. Therefore, it would appear that steady-state concentrations do not change follow-ing prolonged administration. Data obtained after 4 to 6 weeks' treatment with 20 to 80 mg/day in patients with depression showed no clinically im-portant differences, when male and female de-pressed patients were compared, or when these data were further stratified according to age (Bergstrom et al. 1986b).

5.1 Polymorphic Metabolism

Debrisoquine and sparteine or dextro-methorphan oxidation polymorphism has been used to assess interindividual variability in drug metabolism (Sjoqvist 1988). The absence of CYP2D6 enzyme from the liver appears to cause polymorphic metabolism of these 3 compounds (Zanger et al. 1988). Fluoxetine displays a large

206 Clin. Pharmacokinet. (3) 1994

Pharmacokinetics of Huoxetine 207

interindividual variability, and polymorphic oxida-tive drug metabolism may account for this variability (De Vane 1991). More recently in 19 patients receiving fluoxetine, the ratio of O-demethylated dextrometorphan to parent drug (suggestive of CYP2D6 activity) fell into the region of the anti-mode separating the O-demethylation ratio values observed in 208 extensive metabolisers from that observed in a control group of 15 poor metabolisers (Otton et al. 1993). Moreover, fluoxetine and norfluoxetine inhibited the O-demethylation (catalysed CYP2D6) of oxycodone to oxymor- phone in hepatic microsomes from both individuals who were both extensive metabolisers and those who were poor metabolisers of the drug. This indicates that fluoxetine and its metabolite are not selective inhibitors of CYP2D6 activity (Otton et al. 1993), and also that the analgesic effect of oral opietas that are bioactivated by CYP2D6 may be impaired during treatment with fluoxetine. It should be stressed that as all the 5-HT reuptake inhibitors affect the activity of microsomal CY2D6 to varying degrees, the relevant clinical implications for individuals drugs will differ. Individuals who were poor metabolisers of fluoxetine (t½β greater than 3 days after a single dose) were shown to be poor metabolisers of dex-tromethorphan. Furthermore, poor metabolisers of debrisoquine were also poor metabolisers of fluoxetine. These results suggest that fluoxetine pharmacokinetics are influenced by the type of polymorphic oxidative metabolism characteristic of debrisoquine and dextromethorphan metabo-lism (Brøsen & Skjelbo 1991). The main conse-quence of CYP2D6 inhibition is that fluoxetine (and paroxetine) inhibit their own metabolism, thus, showing a non-linear pharmacokinetic pro-file the dose is increased (see section 5).

6. Pharmacokinetics in Special Population 6.1. Elderly Patients

When a single dose of fluoxetine 40mg was ad-ministered orally to 11 healthy elderly male and female volunteers (age ranging from 65 to 77

years), the pharmacokinetics of fluoxetine and norfluoxetine did not differ from those in younger volunteers (Bergstrom et al. 1983). The lack of age-related differences is clinically important be-cause the elimination of tricyclic and atypical an-tidepressant drugs can be reduced, and the bio-availability of these drugs can be increased, in elderly patients (Altamura et al. 1982, 1983; Nies et al. 1977),

6.2 Patients with Renal Impairment

Renal impairment does not significantly affect the pharmacokinetics of fluoxetine, because meta-bolism is the rate-controlling process in the dispo-sition of this drug. The pharmacokinetic profile of fluoxetine was not significantly different in pa-tients with varying degrees of renal impairment. Patients with creatinine clearance values of >90, 10 to 70, or <10 ml/min (>5.4, 0.6 to 4.2, or <0.6 L/h. had a t½β of 3.6, 4.8 or 1.8 days, CL of 20.8, 17.3 or 29.2 L/h and Vd of 25.8,36.5 or 24.0 L/kg, respectively (Aronoff et al. 1984) [fig. 3]. These differences, however, were not significant.

6.3 Patients with Hepatic Dysfunction

The pharmacokinetics of fluoxetine were af-fected by hepatic dysfunction. The ty2p was signif-

Fig.3 Pharmacokinetic parameters of fluoxetine in patients with varying degrees of renal impairment (data from Aronoff et al. 1984). Abbreviations: CL = total body clearance; Vd = apparent volume of distribution.


icantly longer (7.6 vs 2.8 days) and CL was lower (14.5 vs 45.31 L/h) in patients with alcohol (etha-nol)-related cirrhosis of the liver than in individuals with normal hepatic function. The Vd was similar in patients with cirrhosis and healthy individuals (46.8 and 42.5 L/h, respectively) [Schenker et al. 1988].

6.4 Obese Patients

The pharmacokinetic profiles of fluoxetine and norfluoxetine in obese individuals were similar to those observed in lean individuals (data on file, Eli Lilly). Steady-state plasma concentrations are un-likely to change significantly as patients lose or gain body weight because it appears that fluoxetine and nortluoxetine do not readily distribute into ad-ipose tissue (data on file, Eli Lilly).

7. Concentration-Response Studies

Interest in the use of plasms fluoxetine concen-trations to rationalise clinical response stemmed from evidence that platelets harvested from healthy volunteers inhibited tritiated 5-HT uptake by 65%. Furthermore, the inhibition of uptake cor-related positively with plasma fluoxetine concen-trations (Lemberger at al. 1985).

Most studies have found a possible therapeutic window for fluoxetine. In fact, combined plasma concentrations of fluoxetine plus norfluoxetine above 500 µg/L seem to be associated with a poorer response than lower plasma concentrations. How-ever, because of study design factors such as in-creasing doses study duration, sample size, etc., some studies (e.g. Beasley et al. 1990; Kelly et al. 1989; Martensson et al. 1989) have not found a concentration-response relationship for fluoxetine.

Montgomery et al. (1986) were the first to pro- vide evidence of a therapeutic window for fluoxet-ine. They studied the plasma concentration-response relationship in 2 groups of patients. The first group was treated with fluoxetine 60mg daily, and the second group of patients received fluoxetine 80mg once weekly. In the former group, mean plasma concentrations ranged from 200 to 531 µg/L for fluoxetine and from 103 to 465 µg/L for

norfluoxetine after the first week of therapy. No relationship was seen between plasma fluoxetine concentration and response, but a significant neg-ative relationship was observed between plasma concentrations of norfluoxetine and response. The group of patients that responded at the end of the study had significantly lower plasma norfluoxetine concentrations than non-responders. This finding almost exactly parallels that reported for the anti-depressant norzimeldine, and suggests that the dos-age of fluoxetine was too high in the group of pa-tients receiving the drug daily (Montgomery et al. 1990).

The plasma concentrations of norfluoxetine achieved in the patients receiving fluoxetine once- weekly were in the same range as those observed in patients receiving fluoxetine 60mg daily who responded to therapy. As expected plasma concen-trations of fluoxetine were very low, thus suggest-ing that fluoxetine scarcely contributed to the therapeutic response. Indeed, it would seem that the active pharmacological agent may be norfluoxetine. Since this study included only 20 patients in each group, firm conclusions cannot be drawn. However, the hypothesis that the optimal dosage of fluoxetine dosage is less than 60mg daily should be considered.

Subsequently, Goodnick (1991) found that, of 15 patients receiving fluoxetine 20 to 80 mg/day 9 patients had combined plasma fluoxetine plus norflouxetine concentrations of 200 to 499 µg/L. The Beck Depression Inventory decreased by 50% in 6 of these 9 patients, whereas none of these 6 had plasma fluoxetine plus norfluoxetine concen-trations above 500 µg/L.

It is unclear whether common adverse effects of fluoxetine, including nausea, are related to plasma concentrations of the drug. However, it is clear that with higher dosages of the drug, the incidence of nausea and vomiting increases (Altamura et al 1988). Data from patients who had taken an over-dosage show that combined plasma concentrations of fluoxetine plus norfluoxetine must exceed ther-apeutic concentrations by several-fold before seri-


ous complications arise (Kincaid et al. 1990; Roett - ger 1990; Rohrig & Prouty 1989). In summary, routine determination of plasma fluoxetine concentrations are not necessary, but may be warranted to check compliance. They may also be used in the case of overdosage, when fluoxetine is used in combination with monoamine oxidase inhibitors (see section 8), and when pa - tients do not respond to standard daily dosages of the drug. Of course, when a patient fails to respond to therapy, clinical factors should also be consid - ered, (Altamura 1990, 1991). In ou r experience, a dosage that is too high can be as ineffective as one that is too low. Furthermore, it has been hypothesised that suicidal ideation may occur as a of high plasma fluoxetine concentratioris (Fichtner et al.1991).

8. Drug Interactions

Fluoxetine can interact with different classes of antipsychotic drugs. Because of the long t½β of fluoxetine and norfluoxetine (Benfield et al, 1986), drug interactions may oc cur several weeks after fluoxetine therapy has been discontinued. Signs of tricyclic antidepressant toxicity, including seda - tion, decreased energy and alertness, tinnitus, memory impairment and dry mouth, have been re - ported to occur 1 to 2 weeks after fluoxetine was combined with nortriptyline or desipramine (Goodnick 1989; Vaughan 1988). Fluoxetine sig - nificantly increased the t½β and plasma concentra - iton tricyclic antidepressants when the 2 drugs were given concurrently (Jarvis 199 1; von Ammon Cavanaugh 1990). It appears that fluoxetine causes an inhibition of tricyclic 2 -hydroxylation and de - creases first-pass and systemic metabolism of tri - cyclic antidepressant drugs (Bergstrom et al 1 9 9 2 ) .

I n v i t r o ( B l o o m e r e t al. 1991) and in vivo (Sindrup et al. 1991) studies have demonstrated that SSRIs are also a substrate for CYP2D6 (see section 5.1). Recent reports suggest that paroxet - ine, fluoxetine and other members of this alass in - inhibit CYP2D6 (Brøsen & Skjelbo 1991; Preskorn 1993). Inhibition of CYP2D6 -catalysed metabo-

lism can lead to alteration in pharmacokinetic profile of CYP2D6 substrates. Because tricyclic antidepressants require biotransformation medi- ated by CYP2D6 prior to excretion (Potter & Manji 1990), they can be used to test the in vivo effect of concomitant administration of drugs such as fluoxetine, paroxetine and sertraline on CYP2D6-metabolism (Brøsen et al. 1992). In studies under-taken with desipramine, fluoxetine and paroxetine both 20 mg/day caused greater than a 400% reduc- tion in the CL of desipramine, and consequently important increases in the plasma concentration of the drug. In contrast, sertraline 50 mg/day had a negligible effect (i.e. < 30% change in clearance of the tricyclic antidepressant) [Preskorn 1993]. Al-though both paroxetine (20 mg/day) and fluoxetine (20 mg/day) had a similar effect on the CL of de-sipramine, the effect of paroxetine will be shorter because it has a shorter half-life. However, higher dosages of paroxetine will result in a prolonged and enhanced effect due to the nonlinear pharma-cokinetics of paroxetine (Preskorn 1993). For those substrates with a narrow therapeutic range, this interaction could have clinical significance. Human hepatic microsomes were used in in vitro studies to compare the inhibitory potency of SSRIs. Paroxetine was the most potent inhibitor, on a molar basis, of the CYP2D6-catalysed oxidation of sparteine [inhibitory rate constant (Ki) of 0.15 µmol/L]. However, fluoxetine (Ki = 0.60 µmol/L) and sertraline (Ki = 0.70 µmol/L) had Ki

values in the same range. Fluvoxamine (Ki = 8.2 µmol/L) and citalopram (Ki = 5.1 µmol/L) also in-hibited CYP2D6 activity, but to a lesser extent than did paroxetine or fluoxetine. Although the major metabolites of paroxetine produced negligible in-hibition, norfluoxetine was a potent CYP2D6 in-hibition (K i = 0.43 µmol/L). CYP2D6 was also inhibited by tricyclic antidepressant drugs, including clomipramine (Ki = 2.2 µmol/L), desipramine (Ki = 2,3 µmol/L) and amitriptyline (Ki = 4.0 µmol/L)

As a consequence of inhibition of CYP2D6, when imipramine or desipramine are codminis- tered with fluoxetine, a lower dosage of the tricy-clic antidepressants may be needed to avoid ad-


verse effects caused by increased tricyclic antidepressant concentrations (Eisen 1989; Preskorn et al. 1990; Wilens et al. 1992). It is predicted that plasma fluoxetine concentrations will not increase, because fluoxetine is a more potent inhibitor of CYP2D6 than is the tricyelic antidepressant. Fur- thermore, it is likely that this combination will be used clinically, because the combination can re- duce the latency of antidepressant response (Al- tamura 1991; Nelson et al. 1991) or improve response in patients who are resistant to the individual therapies (Eisen 1989; Suckow et al. 1992a).

Pharmacodynamic interactions between fluoxetine and antidepressants may also occur. For example, when a monoamine oxidase inhibitor and fluoxetine are used in combination a 'serotonergic syndrome' has resulted (Ciraulo & Shader 1990). This syndrome is characterised by gastrointestinal (abdominal cramping), neurological (tremulous-ness, myoclonus, dysarthria, incoordination), car-diovascular (tachycardia, hypertension), and psy-chological (confusion, mania-like symptoms, etc.) symptoms. It is also associated with other vegeta-tive symptoms (e.g. diaphoresis). Coma and possi-bly death from heart block or cardiovascular col-lapse can also occur (Boyer & Feighner).

There have been a number of reports of serious adverse reactions, including 4 deaths from what appeared to be neuroleptic malignant syndrome, when monoamme oxidase inhibitors were admin-istered soon after fluoxetine treatment was with-drawn. Therefore, the manufacturer recommends that monoamine oxidase inhibitors are not intro-duced until 5 weeks after discontinuation of fluoxetine.

There have also been occasional reports of in-teractions between fluoxetine and both tryptophan and lithium, resulting in restlessness, agitation and movement disorders (Committee on Safety of Medicines 1989). Therefore, although these com-binations are potentially beneficial, they should be used cautiously.

Fluoxetine has been reported to interact with both diazepanm and alprazolam (table II), although

the drug does not appear to interfere with the nitroreduction of clonazepam (Greenblatt et al. 1992) or the disposition of triazolam (Wright et al. 1992). However, investigators recommended that patients' clinical response to therapy be monitored when triazolam is administered concurrently with fluoxetine (Wright et al. 1992). Another report in-dicated that fluoxetine may have blocked the an-xiolytic effects of buspirone (Bodkin & Teicher 1989). Fluoxetine has been shown to interact with carbamazepine (table II). Therefore, concomitant use of these 2 drugs should be accompanied by careful monitoring, because it is likely that fluoxet-ine will cause an increase in the plasma concentra-tion of antiepileptic drugs.

Fluoxetine appears to inhibit the metabolism of antipsychotics. Its use in combination with clozap-ine, haloperidol, pimozide, fluphenazine and per-phenazine has been associated with potentiation of extrapyrimidal symptoms (Cassady & Thaker 1992; Ciraulo & Shader 1990; Ketai 1993; Lock et al. 1990; Tate 1989). A recent paper from Baldessarini and colleagues (1993) showed that in rats treated with intraperitoneal clozapine, pre-treatment with fluoxetine for 1 week markedly in-creased concentrations of clozapine and its meta-bolite norclozapine in both serum (86%) and brain (61%). These findings are consistent with those ob-served in patients receiving clozapine and fluoxet-ine concomitantly (Centorrino et al. 1994).

The addition of the narcotic pentazocine to fluoxetine treatment is potentially dangerous, lead-ing to severe CNS excitatory responses (Hansen et al. 1990). The effect of fluoxetine on psychomotor performance, physiological response, and pharma-cokinetic disposition of alcohol have been exam-ined. Fluoxetine (30 or 60mg) administered with alcohol (45 ml absolute alcohol per 70 kg body-weight) did not alter the plasma fluoxetine concentrations or the blood alcohol concentrations compared with concentrations obtained, after ad-ministration of either drug alone. Furthermore, there was no significant effect on standing or re-cumbent blood pressure or heart rate after single or multiple doses of fluoxetine were administered ei-

ttf Fluoxetine 211

(F)

ther alone or in combination with alcohol. Single or multiple doses of fluoxetine had no effect on the pasychomotor activity (stability of stance, motor performance, manual coordination) or subjective effects alcohol. (Lemberger et al. 1985).

9. Conclusions

Fluoxetine, and its major metabolite norfluoxet- Ine, block 5-HT reuptake in the CNS, to produce a clinical effect. The unusual pharmacokinetic profile of this drug appears to influence its therapeutic efficacy.

Fluoxetine is well, absorbed after oral adminis-tration, and Cmax values are reached 6 to 8 hours postdose. Foof reduces the rate, but not extent, of absorption. Fluoxetine is highly protein bound, with a large Vd. The drug has a long t½β of 1 to 4 days, while norfluoxetine has an even longer t½β. (7 to 15 days). Because of its long t½β, multiple daily dose are unnecessary in the treatment of acute deperssion. Furthermore, it would be expected that occasional noncompliance would cause

little fluctuation in plasma fluoxetine concentra-tions (Altamura & Percudani 1993).

Because fluoxetine has nonlinear pharmacokinetics and a long t1/2, the dosage regimen for elderly patients or those with a reduced metabolic capacity should be carefully selected. Further- more, the ability of fluoxetine to inhibit metabolism of other psychotropic drugs (e.g.tricyclic antidepressant drugs) may lead to an increased incidence of adverse effects when combination therapy is employed (despite continued use of standard daily doses). The combination of fluoxetine with monoamine oxidase inhibitors, lithium or tryptophan is particularly dangerous because these compounds have a synetgisic, effect on-the 5-HT pathways. THe association of fluoxetine with a tricyclic antidepressant drug seems to increase the speed and consistency of antidepressant response. The combination could be clinically useful in the treatment of patients who do not respond to tricyclic antidepressant monotherapy. With this exceptipn,


the coadministration of fluoxetine with other psy-chotropic medications should be avoided, particu-larly in the elderly and in individuals with concom-itant somatic disorders.

In the elderly, the possible disadvantages to ad-ministering fluoxetine (e.g. nonlinear pharmacoki-netics and long t) are counterbalanced by the ob- vious advantages of the drug over tricyclic antidepressants (e.g. superior tolerability profile). Furthermore, because age per se does not influence the disposition of fluoxetine, this drug may be par-ticularly useful for treating depression in the el-derly.

The t½β of fluoxetine is not significantly changed by renal impairment or obesity, but it is. altered in patients with cirrhosis.

It appears that there may be a concentration-ef-fect relationship for fluoxetine. In fact, plasma concentrations of fluoxetine plus norfluoxetine above 500 g/L seem to be associated with poorer response than lower concentrations. Therefore, fluoxetine 20 to 40 mg/day should result in a sat-isfactory clinical response, while avoiding the risk of overdosage (particularly in elderly patients).

In conclusion, a complete understanding of the pharmacokinetic profile of fluoxetine is necessary for optimal clinical use of this drug. Such an un-derstanding has the potential to minimise adverse effects that often arise from the unnecessary use of combination treatments.

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Clinical Pharmacokinetics of Fluoxetine

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