Metabolism and Pharmacokinetic Properties of SSRIs

The SSRIs differ widely in their chemical structure (Fig. 2.1) which explains the differences in their pharmacological profile regarding inhibition of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake by nerve endings. Fluoxetine and citalopram are produced commercially as racemates. Figure 2.2 shows that uptake inhibition of both 5-HT and noradrenaline displays stereoselectivity when the chiral compounds citalopram and fluoxetine and their metabolites are considered.10 Citalopram and fluoxetine have active metabolites but, most probably, only norfluoxetine has to be considered as a clinically relevant metabolite. Sertraline is the most potent 5-HT uptake inhibitor, and S-citalopram is the most selective of these agents with regard to 5-HT as compared to noradrenaline uptake inhibition. SSRIs also present some interindividual differences with regard to their affinity for adrenergic, muscarinic, histaminic and serotonergic receptors as well as for 5-HT and noradrenaline transporters,11,12 but data are scarce regarding these properties for the enantiomers of the chiral SSRIs.

Cytochrome P450 of the liver contributes, to a large extent, to the metabolism of SSRIs but the role of the isozymes implicated in this process varies considerably from one compound to another.

As summarized in Table 2.1, a genetic polymorphism has been described for two of these cytochromes, CYP2D6 and CYP2C19. Patients who, for genetic reasons, are unable to metabolize substrates of these enzymes undergo a higher risk of adverse effects when treated with such drugs.13 In the case of CYP2D6, gene amplification has been demonstrated which explains the existence of ultrarapid metabolizers.14,15 Debrisoquine, sparteine and dextromethorphan are the drugs which are commonly used for CYP2D6 phenotyping.

Selective Serotonin Reuptake Inhibitors (SSRIs): Past, Present and Future, edited by S. Clare Stanford. ©1999 R.G. Landes Company.

Fig. 2.1. Chemical formulae and N-demethylation pathway of SSRIs.

Caffeine, mephenytoin and dextromethorphan (or midazolam) are used as test probes for measuring CYP1A2, CYP2C19 and CYP3A4 activity, respectively. Subjects may be genotyped for CYP2D6 or CYP2C19 with appropriate molecular biological techniques.13,16 There is a high interindividual variability in the activity of CYP1A2 and CYP3A4. Furthermore, these enzymes can be induced by exogenous factors, such as tobacco smoke (CYP1A2) and drugs like carbamazepine and barbiturates (CYP3A4) (Table 2.1). CYP1A2, CYP2D6, CYP2C19, CYP3A4, and possibly CYP2C9, are the main enzymes involved in the metabolism of SSRIs, albeit to variable degrees (Fig. 2.3).

Fig. 2.2. 5-HT and noradrenaline reuptake inhibition properties of SSRIs at the synaptic level (as described by Baumann and Rochat, 1995).10
Table 2.1. Properties of cytochrome P450 isozymes involved in the metabolism ofSSRIs and/or inhibited by SSRIs

Isoenzyme

Genetic polymorphism

% Poor metabolizers (Europe)

Isozyme inducible

Typical substrates inhibitors

CYP1A2

no

-

(tobacco-smoke)

caffeine clozapine

fluvoxamine

CYP2C9

yes

rare

(anticonvulsants)

phenytoin

sulfaphenazole

CYP2C19

yes

3-5

no (?)

mephenytoin diazepam

omeprazol

CYP2D6

yes

5-10 (*)

no

dextromethorphan debrisoquin, sparteine

thioridazine quinidine

CYP3A4

no

-

(carbamazepine)

triazolam

erythromycine

(*): also ultrarapid metabolizers (1-7 % of the population) (gene amplification)

(*): also ultrarapid metabolizers (1-7 % of the population) (gene amplification)

S.R-FLUO

S.R-FLUO

?: end product unknown

---: probable pathway

?: end product unknown

---: probable pathway

Fig. 2.3. Role of cytochrome P450 isozymes in the biotransformation of SSRIs. CIT: citalo-pram; DCIT demethylcitalopram; FLUO: fluoxetine; FLUV: fluvoxamine; PAR: paroxetine; SER: sertraline.

There is now evidence that racemic fluoxetine is N-demethylated to norfluoxetine17 and sertraline to norsertraline18 by CYP2C9 in vitro. The role of this enzyme in the metabolism of these and other SSRIs remains to be clarified but it is actually inhibited by some of these compounds.19 As shown in Figure 2.3, the limitations of our present knowledge are striking. This is particularly the case when considering the nature of the most important metabolites of SSRIs as well as the exact mechanisms or enzymes leading to their formation. Several review papers have recently been published on the metabolism and pharmacokinetics of the SSRIs (Table 2.2).20-23

Citalopram

Citalopram is a tertiary amine (Fig. 2.1) which is N-demethylated to demethylcitalopram and didemethylcitalopram. These metabolites are also SSRIs but plasma concentrations of N-didemethylcitalopram are extremely low in clinical conditions. Recently, we have shown that the propionic acid derivative of citalopram, an inactive metabolite, is formed by the enzyme, monoamine oxidase (MAO; see below).36 The S-enantiomers of citalopram and the N-demethylated metabolites are more potent than the R-enantiomers in inhibiting 5-HT reuptake (Fig. 2.2).37 Taking account of the plasma concentrations observed in clinical conditions, S-citalopram has therefore to be considered as the pharmacologically relevant compound.38,39

The first in vivo studies on the role of cytochrome P450 in the metabolism of citalo-pram produced evidence for control of N-demethylation of racemic citalopram and demethylcitalopram by CYP2C19 and CYP2D6, respectively (Fig. 2.3).40 In studies of human liver microsomes and cytochrome P450 isozymes expressed by cDNA in human B-lympho-blastoid cell lines in vitro, we demonstrated that the enantiomers of citalopram

Table 2.2. General comparative pharmacokinetics of SSRIs

SSRI Active metabolites

Cmax (ng/ml) (after mg single dose)

Tmax

(h)

T1/2 (h) plasma

(%)

Cl/F (ml/min)

References

Citalopram Demethylcitalopram

39(40)

2-4

(23-75) 33 ± 7 51.7 ± 8.0 (a) 101.1 ± 23.1 (a)

12-16

80

20

378 ± 65

24-26

Didemethylcitalopram

Fluoxetine Norfluoxetine

15-55 (30 or 40)

6-8

7-15

12-43 11-88

ca 70

5.5

94-703

27-28

Fluvoxamine

14 ± 4 (50) (b)

7.8 ± 2.4 (b)

11.7 ± 3.0 (b)

5

53

23

3000 ± 1200 (b)

29-30

Paroxetine

10.7 ± 10.4 (20)

5.8 ± 1.7

7-65

8-28

ca 50

5

1230-7720 (c)

31-34

Sertraline Norsertraline

118 ± 22 (m); 166 ± 65 (f); 200 (*) 156 ± 36 (m); 244 ± 80 (f)

9.1 ± 3.0 (m); 5.9 ± 3.1 (f)

79

>20

1.5

23.5 ± 6 (m); 22.5 ± 11.1 (f)**

35 and Pfizer, data on file

Data, if available, are presented as means ± s.d. or ranges: d (days) m (male ), f (female)

(a): in subjects co-medicated with cimetidine (ref. 26); (b): in 10 extensive metabolizers of dextromethorphan and non-smokers (ref. 29); (c) (ref. 34); *: after 30 days of treatment; ** ml/min/kg.

Clincial Pharmacokinetics of SSRIs

15

Table 2.3. Comparative pharmacokinetics of the chiral SSRIs Citalopram and fluoxetine in phenotyped (CYP2D6) healthy subjects

SSRI

PMs References

S-citalopram

34.8 ± 4.3*

39

R-citalopram

46.9 ± 10.6

S-demethylcitalopram

50.6 ± 12.7*

R-demethylcitalopram

69.8 ± 18.8

S-fluoxetine

26.7

147.1** 44-45

R-fluoxetine

63.5

227.6*

S-norfluoxetine

131.8

417.6**

R-norfluoxetine

132.9

166.3 n.s.

(a) for citalopram, means ± s.d.; for fluoxetine, median values Citalopram study, comparison S- versus R-enantiomers; *,P<0.05 Fluoxetine study, Mann-Whitney, EMs vers PMs; *,P<0.05; **,P<0.01 EMs and PMs, extensive and poor metabolizers of sparteine, respectively.

are stereoselectively N-demethylated. CYP2D6 preferentially N-demethylates R-citalopram but its role is minor in the overall metabolism by cytochrome P450. S-citalopram is preferentially metabolized by CYP3A4 and CYP2C19.41 We observed that, in patients submitted to a citalopram treatment, the ratio of S/R-citalopram averages about 0.5 in plasma at steady-state conditions.38,42,43 This ratio reaches unity in patients with a genetic deficiency of CYP2C19 (Baumann et al, in preparation).A pharmacokinetic study on the fate of the enantiomers of citalopram at steady-state conditions (Table 2.3) shows that, in extensive metabolizers of sparteine (CYP2D6) and mephenytoin (CYP2C19), the pharmacologically relevant enantiomer, S-citalopram, has a shorter plasma half-life than does R-citalopram.39 This is probably explained by the fact that CYP2C19 preferentially demethylates S-citalopram.

Citalopram is the only SSRI available for intravenous treatment. In our study of the hormonal effects of an intravenous infusion of citalopram (20 mg) in healthy volunteers, the only measurable metabolite in plasma was its propionic acid derivative.46 It has therefore to be considered as an important metabolite but, until recently, no data were available on the mechanism of its formation. Our in vitro studies with human liver suggest that MAO-A and MAO-B and aldehyde oxidase stereoselectively control the deamination of citalopram and its N-demethylated metabolites and that, in this respect, N-demethylcitalopram appears to be the best substrate.36 The S-enantiomers are preferentially metabolized by MAO-B, and the R-enantiomers by MAO-A. The biotransformation of citalopram is strongly inhibited by the MAO-A inhibitor, clorgyline, and that of didemethylcitalopram by the MAO-B

inhibitor, selegiline. This seems to be the first demonstration that MAO is involved in the metabolism of psychotropic drugs which are used therapeutically. It remains to be demonstrated whether other drugs of this family are also metabolized by MAO but, for fluoxetine47 and sertraline at least, deaminated metabolites have been described. With regard to its pharmacokinetic properties, and in comparison with other SSRIs, citalopram is the antidepressant with the highest bioavailability (about 80%) (Table 2.2). This explains why, in our comparative study of the clinical effectiveness of intravenous versus oral citalopram (40 mg/day) in depressive patients, the concentrations of citalopram in plasma at steady-state conditions did not differ between the two groups of patients.49

Fluoxetine

The secondary amine, fluoxetine, is N-demethylated to norfluoxetine (Fig. 2.3) which is also a potent and selective 5-HT uptake inhibitor. S- and R-fluoxetine and S-, but not R-norfluoxetine, have to be considered as SSRIs in view of their pharmacological profile (Fig. 2.2).50,51 In clinical conditions, the ratio of S/R-fluoxetine varies from 0.93-3.63, and that of S/R norfluoxetine from 1.58-3.32.52 The existence of a stereoselective metabolism of fluoxetine has been confirmed recently in that the R-enantiomers are more rapidly metabolized and eliminated than the corresponding S-enantiomers (Table 2.2). CYP2D6 contributes to the metabolism of fluoxetine and norfluoxetine, as shown in a panel study with healthy volunteers.53 So far, it is unknown which pathway is concerned but it could be O-dealkylation.47,54 We observed that, in poor metabolizers of sparteine (CYP2D6 deficiency), the elimination of S- and R-fluoxetine and of S-norfluoxetine, but not R-norfluoxetine, is impaired.44,45 Possibly, in such patients, the occurrence of adverse effects may be more frequent: interestingly, an elderly depressive patient with a genetic deficiency of CYP2D6 has been described who suffered from a choreiform syndrome while treated with fluoxetine but no drug plasma concentrations were measured, unfortunately.55 In vitro studies with racemic fluoxetine suggest that CYP2C9 is the main enzyme implicated in N-demethylation of fluoxetine to norfluoxetine while CYP2C19, CYP2D6 and CYP3A play a minor role. Fluoxetine does not seem to be metabolized by CYP1A2 (Fig. 2.3).17

Fluvoxamine

No active metabolite is known for the primary amine antidepressant, fluvoxamine. A panel study with healthy, non-smoking volunteers, previously phenotyped with dextromethorphan (CYP2D6) and mephenytoin (CYP2C19), suggests that CYP2D6 but not CYP2C19 plays some minor role in the metabolism of fluvoxamine.29 CYP1A2, an enzyme induced by tobacco-smoking, could also contribute to the metabolism of fluvoxamine because elimination of fluvoxamine is more rapid in smokers than in non-smokers.56 There is no direct evidence of the metabolites which are formed under the influence of cytochrome P450 (Fig. 2.3). Fluvoxamine is the SSRI with the shortest plasma half-life (Table 2.2).

Paroxetine

None of the metabolites of the secondary amine antidepressant, paroxetine,5 seem to be active with regard to 5-HT uptake inhibition.57 Paroxetine is transformed to hydroxylated metabolites and then glucuronidated. Catechol-O-methyltransferase (COMT) probably contributes to the formation of catechol metabolites. The metabolism of paroxetine is under the genetic control of CYP2D6, as shown in a panel study (Table 2.2).33 This could explain the wide interindividual variability in the elimination kinetics of paroxetine. CYP2D6 could be involved in the oxidation of the methylenedioxyphenyl ring but direct evidence seems to be missing. Paroxetine displays non-linear kinetics, and probably other P450 isozymes contribute to its metabolism.34

Sertraline

Sertraline, a secondary amine (Fig. 2.1), is N-demethylated to the weakly active SSRI, norsertraline. Although the mechanism has not yet been clearly elucidated CYP3A453 and CYP2C9,18 but not CYP2D6, are probably involved (Fig. 2.3). Another inactive metabolite is a ketone which could be formed by deamination (c.f., citalopram).48

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