Metabolic drug interactions with new psychotropic
agents
Edoardo Spina*, Maria Gabriella Scordo, Concetta D’Arrigo
Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina,
Policlinico Universitario, Via Consolare Valeria, 98125 Messina, Italy
ABSTRACT
New psychotropic drugs introduced in clinical practice in recent years
include new antidepressants, such as selective serotonin reuptake
inhibitors (SSRI) and ‘third generation’ antidepressants, and atypical
antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine,
ziprasidone and amisulpride. These agents are extensively metabolized in
the liver by cytochrome P450 (CYP) enzymes and are therefore
susceptible to metabolically based drug interactions with other
psychotropic medications or with compounds used for the treatment of
concomitant somatic illnesses. New antidepressants differ in their
potential for metabolic drug interactions. Fluoxetine and paroxetine are
potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2
and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These
antidepressants may be involved in clinically significant interactions
when coadministered with substrates of these isoforms, especially those
with a narrow therapeutic index. Other new antidepressants including
sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak
in vitro inhibitors of the different CYP isoforms and appear to have less
propensity for important metabolic interactions.
1
The new atypical antipsychotics do not affect significantly the activity of
CYP isoenzymes and are not expected to impair the elimination of other
medications. Conversely, coadministration of inhibitors or inducers of the
CYP isoenzymes involved in metabolism of the various antipsychotic
compounds may alter their plasma concentrations, possibly leading to
clinically significant effects. The potential for metabolically based drug
interactions of any new psychotropic agent may be anticipated on the
basis of knowledge about the CYP enzymes responsible for its
metabolism and about its effect on the activity of these enzymes. This
information is essential for rational prescribing and may guide selection
of an appropriate compound which is less likely to interact with already
taken medication(s).
INTRODUCTION
A drug interaction occurs when the effectiveness or toxicity of a drug is
altered by the concomitant administration of another drug. In some cases
drug interactions may prove beneficial, leading to increased efficacy or
reduced risk of unwanted effects. However, more often, drug interactions
are of concern because the outcome of concurrent drug administration is
diminished therapeutic efficacy or increased toxicity of one or more of
the administered compounds.
Mechanisms of drug interactions are usually divided into two categories:
pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions
2
consist of changes in the absorption, distribution, metabolism or excretion
of a drug and/or its metabolites, or the quantity of active drug that reaches
its site of action, after the addition of another chemical agent.
Metabolically based drug interactions are the most frequently
encountered of this kind. Pharmacodynamic interactions occur when two
drugs act at the same or interrelated receptor sites, resulting in additive,
synergistic or antagonistic effects.
During the last 10–15 years new psychotropic drugs, in particular,
antidepressants and antipsychotics, have been introduced in psychiatric
practice in the effort to overcome the limitations of older compounds in
terms of both efficacy and tolerabilty. The purpose of this article is to
provide a comparative review of metabolic drug interactions involving
new psychoactive agents. Drug interactions represent an important aspect
in the evaluation of compounds like psychotropic drugs that are usually
administered chronically and often in association with other medications.
Combination pharmacotherapy is commonly used in clinical psychiatry to
treat patients with comorbid psychiatric or somatic disorders, to control
the side effects of a specific drug or to augment a medication effect [1].
Therefore, the use of psychotropic agents with low potential for drug
interactions is desirable, especially for elderly patients who are more
likely to take many medications.
DRUG INTERACTIONS AND THE CYTOCHROME P450
3
SYSTEM
With a few exceptions, psychotropic drugs are lipophilic agents that are
extensively metabolized in the liver through phase I oxidative reactions,
followed by phase II glucuronide conjugation. Most pharmacokinetic
interactions with psychotropic drugs occur at metabolic level and usually
involve changes in the activity of the cytochrome P450 (CYP)
mono-oxygenases. This system consists of a superfamily of isoenzymes
located in the membranes of the smooth endoplasmic reticulum, mainly
in the liver, but also in other organs and tissues (e.g. intestinal mucosa,
lung, kidney, brain, lymphocytes, placenta, etc.) [2,3]. These isoenzymes
are haemoproteins which contain a single iron protoporfyrin IX prosthetic
group. They are responsible for the oxidative metabolism of most drugs
and xenobiotics as well as many endogenous compounds such as
prostaglandines, fatty acids and steroids. The multiple CYP enzymes are
classified into families, subfamilies and isoenzymes according to a
systematic nomenclature based on similarities in their amino acid
sequences [4]. The first Arabic number designates the ‘family’ (>40%
sequence identity within family members), the capital letter that follows
indicates the ‘subfamily’ (>59% sequence identity within subfamily
members), while the second Arabic number designates individual
isoenzymes. The major CYP enzymes involved in drug metabolism in
humans belong to families 1, 2 and 3, the specific isoforms being
4
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Each CYP
isoform is a specific gene product and possesses a characteristic broad
spectrum of substrate specificity. The activity of these isoenzymes is
genetically determined and may be profoundly influenced by
environmental factors, such as concomitant administration of other drugs.
Drug interactions involving CYP isoforms generally result from one of
two processes, enzyme inhibition or enzyme induction [5]. Enzyme
inhibition usually involves competition with another drug for the enzyme
binding site, while enzyme induction occurs when a drug stimulates the
synthesis of more enzyme protein, enhancing the enzyme’s metabolizing
capacity.
In recent years, a great body of research has focused on CYP isoenzymes
and their different substrates, inhibitors and inducers of have been
identified [6] (Table I). As shown in Table I, the majority of new
psychotropic agents are either metabolized by, or inhibit to varying
degrees, one or more CYP isoforms. This information may be of great
value for clinicians to predict and eventually avoid drug interactions. In
fact, there is a potential for metabolically based drug interactions when a
drug metabolized by a specific CYP isoenzyme is given in combination
with another agent that inhibits or induces that enzyme. As a consequence,
plasma concentrations of the coadministered drugs may be increased or
decreased, possibly resulting in clinical toxicity or diminished therapeutic
5
effect. In particular, following administration of an inhibitor and a
substrate of a given CYP isoform, the first pass effect of the substrate
may be reduced with subsequent increase in its oral bioavailability,
elevated plasma levels and exaggerated pharmacological effects.
Drug–drug interactions may be initially studied in vitro in order to predict
the potential importance in vivo. However, it should be emphasized that
only few of all theoretically possible drug interactions are clinically
relevant. As suggested by Sproule et al. [1], several factors must be taken
into account when evaluating the extent and the clinical significance of a
metabolic drug interaction:
1. Drug-related factors: potency and concentration of the
inhibitor/inducer, therapeutic index of the substrate, extent of metabolism
of the substrate through the affected enzyme, presence of active or toxic
metabolites.
2. Patient-related factors: individual inherent enzyme activity (e.g.
phenotyping/genotyping information), risk level for each individual to
experience adverse effects (e.g. the elderly).
3. Epidemiological factors: probability of the interacting drugs being used
concurrently.
Of great concern among these factors is the therapeutic index of the
affected drug. In fact, as a consequence of the same degree of inhibition
or induction, plasma levels of a given substrate are more likely to reach
6
toxic or subtherapeutic values if the substrate has a narrow therapeutic
index, while this is less likely with compounds with a broader therapeutic
index.
METABOLIC DRUG INTERACTIONS WITH NEW
ANTIDEPRESSANTS
Drugs used for the treatment of depressive disorders include older
compounds, such as tricyclic antidepressants (TCAs) and monoamine
oxidase inhibitors, and newer agents, such as selective serotonin reuptake
inhibitors (SSRIs) and other novel antidepressants withvariable
mechanism of action, the so-called ‘third generation’ of antidepressants
[7]. Antidepressants are frequently prescribed in combination with other
central nervous system (CNS) drugs, as well as with medications used to
treat various somatic illnesses. The relevant features of newer
antidepressants for metabolic pharmacokinetic interactions are
summarized in Table II.
SSRIs
The SSRIs represent a relatively new class of antidepressants that are
considered to be comparable in efficacy with TCAs, but with a more
favourable tolerability and safety profile [8]. With regard to potential for
drug interactions, they are at relatively low risk for pharmacodynamically
mediated interactions, but may cause clinically relevant pharmacokinetic
interactions byinterfering with CYP isoenzymes [9,10]. The five
7
marketed SSRIs, namely fluoxetine, fluvoxamine, paroxetine, sertraline
and citalopram, are subject to extensive oxidative metabolism in the liver
[11]. Various drugs may theoretically inhibit or induce the metabolism of
SSRIs, leading to changes in their plasma concentrations. However, these
antidepressants have a wide therapeutic index, so inhibition or induction
of their metabolism is unlikely to be of great concern [10]. However,
SSRIs may cause a clinically relevant inhibition of CYP enzymes and
care must be exercised when adding an SSRI to a multi-drug regimen. As
shown in Table III, the five SSRIs differ considerably in their potency to
inhibit individual CYP enzymes and this may guide selection of an
appropriate compound in the individual patient [12–14]. As the inhibitory
effect on these enzymes is concentration dependent, the potential for drug
interactions is higher in the elderly, particularly for agents whose
elimination is affected by age, such as citalopram and paroxetine, and for
those which exhibit nonlinear kinetics, such as fluoxetine and paroxetine
[11,15,16].
Fluoxetine
Fluoxetine is marketed as a racemic mixture of two enantiomers. The
major metabolic pathway of fluoxetine is N-demethylation to form the
active metabolite norfluoxetine. In vivo studies have indicated that
CYP2D6 is the major isoform responsible for N-demethylation of
fluoxetine [17,18]. However, in vitro evidence suggests that other
8
isoenzymes including CYP2C9, CYP2C19 and Table III Inhibitory effect
of new antidepressants on CYP isoenzymes. Based on Nemeroff et al.,
Greenblatt et al., and Shad and Preskorn [12–14]. CYP3A4 may also
contribute to this reaction [19,20]. Fluoxetine and its metabolite
norfluoxetine have important inhibitory effects on CYP enzymes in vitro.
They were found to inhibit markedly CYP2D6, moderately CYP2C9, and
mildly to moderately CYP2C19 and CYP3A4 [12–14,21–24]. Consistent
with this in vitro evidence, fluoxetine may be involved in clinically
relevant pharmacokinetic interactions with other medications in vivo. In
this respect, due to the long elimination half-lives of fluoxetine and
norfluoxetine, inhibition of CYP enzymes may persist for weeks after
discontinuation of the antidepressants, a situation that complicates the
management of patients [10,11].
A clinically relevant interaction may occur between fluoxetine and some
antidepressants. Fluoxetine, 20–60 mg/day, may cause a two- to four-fold
increase in plasma concentrations of TCAs, possibly associated with
signs of toxicity including decreased energy, psychomotor retardation,
sedation, dry mouth and memory loss [25–29]. The mechanism of this
interaction may be attributed to the potent inhibitory effect of fluoxetine
and norfluoxetine on the CYP2D6-mediated hydroxylation of TCAs.
When given in combination with the heterocyclic antidepressant
trazodone, fluoxetine was found to produce a significant elevation in
9
plasma levels of both trazodone and its metabolite
meta-chlorophenylpiperazine (mCPP) [30]. This is probably caused by
the inhibition of CYP2D6 and CYP3A4 in the metabolism of trazodone
and CYP2D6 inhibition of mCPP metabolism. Fluoxetine has been
reported to produce a remarkable increase in plasma concentrations of
traditional antipsychotics such as haloperidol and fluphenazine,
metabolized at least in part by CYP2D6, possibly leading to CNS side
effects such as extrapyramidal symptoms and impairment of psychomotor
performance [31,32]. Fluoxetine may also interfere with the elimination
of some new atypical antipsychotics. An increase by approximately
50–100% in plasma concentrations of clozapine, an atypical antipsychotic
metabolized by CYP1A2 and, to a lesser extent, by CYP3A4, CYP2D6
and CYP2C19, has been described, following coadministration with
fluoxetine, 20 mg/day [33,34]. In a recent investigation of nine psychotic
patients stabilized on risperidone, another novel antipsychotic whose
metabolism is largely dependent on CYP2D6 and CYP3A4, concomitant
treatment with fluoxetine, 20 mg/day, was associated with a mean
fourfold increase in plasma concentration of risperidone, while the levels
of the active metabolite 9-hydroxyrisperidone (9-OH-risperidone) were
largely unaffected [35]. As a consequence of these changes, the active
fraction of risperidone (sum of plasma concentrations of risperidone and
its active metabolite) increased by 76% over pretreatment. One patient
10
dropped out after 1 week of combination treatment due to the occurrence
of akathisia, while two patients developed parkinsonian symptoms, so
thus requiring anticholinergic medication. Another study has provided
evidence for the pharmacokinetic interaction between fluoxetine and
risperidone [36].
Fluoxetine may also impair the elimination of some benzodiazepines such
as diazepam and alprazolam, through inhibition of the major isoforms
mediating their metabolism, in particular CYP2C19 (diazepam) and
CYP3A4 (diazepam, alprazolam) [37–39]. However, as benzodiazepines
have a wide therapeutic index, the clinical significance of these
interactions is probably limited.
Fluoxetine and its metabolite norfluoxetine are mild to moderate
inhibitors of CYP3A4, the major enzyme involved in the metabolism of
the anticonvulsant and mood stabilizer agent carbamazepine. However,
there is conflicting evidence for an interaction between these two drugs.
Some case reports have documented an increase in plasma carbamazepine
levels, possibly associated with toxic effects, following administration of
fluoxetine [40,41]. Conversely, no modifications in steady-state plasma
concentrations of carbamazepine and its epoxide metabolite were
observed in eight epileptic patients when fluoxetine, 20 mg/day, was
added for 3 weeks [42]. To explain these discrepancies it may be
hypothesized that the inhibitory effect of fluoxetine on carbamazepine
11
metabolism might occur only at higher fluoxetine doses. Fluoxetine may
impair the elimination of phenytoin, as documented by many case reports
of toxic phenytoin concentrations occurring shortly after the addition of
fluoxetine [43–45]. This interaction is probably explained by the
moderate inhibitory effect of fluoxetine on the CYP2C9-mediated
metabolism of phenytoin [46].
A clinically relevant drug interaction may occur between SSRIs and
warfarin, resulting in enhanced anticoagulant activity and subsequent risk
of haemorrhagic complications [47]. Knowledge of the complex
metabolism of warfarin is essential to understand the mechanisms of this
interaction. Warfarin is a racemic mixture with an active S-enantiomer
and an inactive R-enantiomer. The former is metabolized by CYP2C9,
and the latter by CYP1A2 and, to a lesser extent, CYP2C19 and CYP3A4.
In addition to being metabolized by the above isoenzymes, R-warfarin
also inhibits CYP2C9. Concerning fluoxetine, case reports have described
a marked elevation of international normalized ratio and prolongation of
prothrombin time in patients stabilized on warfarin after addition of
fluoxetine [48,49]. The inhibitory effect of fluoxetine on
CYP2C9-mediated metabolism of active S-warfarin is the most likely
explanation for this potentially serious drug interaction. There are isolated
reports of potentially dangerous interactions between fluoxetine and
cardiovascular agents. Inhibition of the oxidative metabolism of
12
betablockers, which is partly mediated by CYP2D6, might explain the
occurrence of severe bradycardia or heart block in two patients after
coadministration of fluoxetine with metoprolol or propranolol [50,51].
The combination of fluoxetine with the calcium channel blockers
nifedipine and verapamil has been reported to be associated with signs of
toxicity such as oedema, nausea and flushing, which disappeared when
doasage of the calcium channel antagonists was reduced [52]. Inhibition
of CYP3A4-mediated metabolism of verapamil and nifedipine by
fluoxetine and its metabolite norfluoxetine may explain the occurrence of
this interaction. Caution is required when administering fluoxetine with
CYP3A4 substrates with a narrow therapeutic index, including cisapride,
astemizole, terfenadine or cyclosporin, as it can lead to potentially serious
adverse effects [53,54]. However, in a formal in vivo study, a daily dose
of 60 mg for 9 days of fluoxetine resulted in no increase in plasma levels
of coadministered terfenadine [55].
Fluvoxamine
The major metabolic pathways of fluvoxamine are oxidative
demethylation and oxidative deamination. At least 11 metabolites have
been identified, none of which seems to possess pharmacological activity.
Although the isoforms involved in its biotransformation are not yet fully
identified, there is in vivo evidence that CYP2D6 and CYP1A2 play a
prominent role [56,57]. Fluvoxamine interacts with several CYP
13
isoenzymes: it is a potent inhibitor of CYP1A2 and CYP2C19 and a
moderate inhibitor of CYP2C9 and CYP3A4, while it affects only
slightly CYP2D6 activity [12–14,22,58,59]. As a result of this
nonselective inhibition of various CYP isoenzymes fluvoxamine has a
high potential for metabolic drug interactions.
Fluvoxamine may increase plasma concentrations of some
antidepressants. Differently from fluoxetine and paroxetine which inhibit
the hydroxylation reactions of TCAs, fluvoxamine affects predominantly
the demethylation pathways of TCAs, through inhibition of CYP2C19
and, to a lesser extent, CYP1A2 and CYP3A4. Accordingly, plasma
levels of tertiary amines amitriptyline, imipramine and clomipramine
have been reported to increase by up to fourfold during coadministration
with fluvoxamine, 100 mg/day, possibly leading to toxic effects, while
concentrations of secondary amine desipramine were only slightly
modified [60–63]. A recent report has documented that addition of
fluvoxamine, 50–100 mg/day, caused a three- to four-fold increase in
plasma concentrations of mirtazapine, a new antidepressant mainly
metabolized by CYP1A2, CYP2D6 and CYP3A4 [64].
Fluvoxamine may interfere with the biotransformation of various
antipsychotics. Addition of fluvoxamine, 50–300 mg/day, to haloperidol
maintenance therapy in schizophrenic patients resulted in 1.8–4.2-fold
increase in serum haloperidol concentrations [65]. This interaction is
14
likely to be explained by the inhibitory effect of fluvoxamine on CYP1A2
and CYP3A4 which are involved in the metabolism of haloperidol.
Clinically relevant metabolic interactions may occur between
fluvoxamine and the atypical antipsychotics clozapine and olanzapine.
Formal kinetic investigations and case reports have clearly documented
that fluvoxamine may increase plasma clozapine concentration up to fiveto 10-fold, possibly resulting in toxic effects [66–69]. Therefore the
combination of fluvoxamine plus clozapine needs to be carefully
supervised and the use of low doses of both compounds is advisable [70].
This interaction is attributed not only to inhibition of CYP1A2, the major
enzyme responsible for clozapine metabolism, but also to additional
inhibitory effects of fluvoxamine on CYP2C19 and CYP3A4 which also
contribute to its biotransformation [71]. Recent studies have reported that
fluvoxamine may also elevate plasma levels of olanzapine by
approximately twofold [72–74]. The potent inhibitory effect of
fluvoxamine on CYP1A2, one of the major isoforms responsible for
olanzapine biotransformation, provides a rational explanation for this
interaction.
Like fluoxetine, fluvoxamine has also been reported to decrease the
metabolic clearance of some benzodiazepines including alprazolam,
which is primarily metabolized by CYP3A4, and diazepam, which is
substrate for both CYP2C19 and CYP3A4 [75,76].
15
The evidence for an interaction between fluvoxamine and carbamazepine
is controversial. Some case reports have indicated that fluvoxamine may
significantly increase plasma concentrations of carbamazepine, with
symptoms of toxicity [77,78]. However, in a study of seven epileptic
patients with depressive symptoms started on fluvoxamine, 100 mg/day,
no change in carbamazepine or carbamazepine-10,11-epoxide
concentrations was observed [42].
Several case reports have documented potentially dangerous
consequences resulting from the combined use of fluvoxamine and
theophylline [79–82]. Concomitant treatment with fluvoxamine may
cause a marked elevation in plasma theophylline levels associated with
signs of theophylline toxicity, including ventricular tachycardia, anorexia,
nausea and seizures. This interaction is presumably mediated by the
inhibitory effect of fluvoxamine on the activity of CYP1A2, which is the
main isoenzyme involved in theophylline metabolism. As theophylline
toxicity is a serious, sometimes fatal, medical condition, fluvoxamine
should be avoided in patients taking theophylline. Even at low daily doses
(10 and 20 mg), fluvoxamine inhibits the metabolism of caffeine, another
methylxanthine, which is used as a probe drug for CYP1A2 [83].
Fluvoxamine may also inhibit the CYP1A2-mediated metabolism of
tacrine, a drug used for the treatment of Alzheimer’s dementia, possibly
increasing its hepatotoxicity [84–86].
16
Apotentially dangerous interaction may occur between fluvoxamine and
warfarin. Addition of fluvoxamine for 2 weeks to a stable regimen with
warfarin produced a 65% increase in plasma warfarin concentration and a
significant prolongation of prothrombin time [87]. Yap and Low [88]
described the case of an elderly woman with atrial fibrillation stabilized
on warfarin, in whom addition of a low dose of fluvoxamine resulted in a
marked elevation of her international normalized ratio that persisted for 2
weeks after stopping the antidepressant. The mechanism of this
interaction is particularly complex. In fact, fluvoxamine may directly
increase plasma levels of S-warfarin through its moderate inhibitory
effect on CYP2C9. In addition, fluvoxamine, a strong inhibitor of
CYP1A2, is expected to elevate levels of R-warfarin, which, in turn,
would reduce CYP2C9 activity and thus increase the effect of the active
S-warfarin [47].
In a study in healthy volunteers, coadministration of fluvoxamine 100
mg/day with propranolol 160 mg/day resulted in a fivefold increase in
plasma propranolol concentrations, associated with a slight potentiation
of the propranolol-induced reductions in heart rate and exercise diastolic
blood pressure [87]. This effect is likely to be the consequence of an
inhibitory effect of fluvoxamine on CYP1A2 and CYP2C19, the major
isoforms involved in the biotransformation of this beta-blocker.
In addict patients on maintenance treatment with methadone, a synthetic
17
opiod predominantly metabolized via CYP3A4, fluvoxamine, but not
fluoxetine, was found to increase by 30–50% plasma concentrations of
both methadone enanatiomers [89,90]. As with fluoxetine, also
fluvoxamine may theoretically cause potentially serious interactions if
coadministered with CYP3A4 substrates.
Paroxetine
Paroxetine undergoes extensive hepatic biotransformation including
oxidative cleavage of the methylenedioxy bridge, resulting in an unstable
catechol intermediate that is further methylated in meta- and
para-position. The oxidative cleavage is mediated by CYP enzymes,
while methylation reactions are probably mediated by
catechol-O-methyltransferase. It is likely that oxidation of paroxetine is
catalysed by a main pathway mediated by CYP2D6, whose saturation is
responsible for the nonlinear kinetics of the drug, and secondary pathway
presumably mediated by CYP3A4, which is usually active for 25% but
becomes prevalent at high concentrations [91,92]. Paroxetine is the most
potent in vitro inhibitor of CYP2D6 among all SSRIs, while it affects
only minimally other CYP isoforms [12–14,21–23]. Moreover, an
intermediate metabolite of paroxetine (M2) has also been shown to have
an inhibitory activity against CYP2D6 [21]. Therefore, paroxetine may
cause clinically relevant drug interactions when coadministered with
CYP2D6 substrates.
18
Like fluoxetine, paroxetine may inhibit CYP2D6-mediated
hydroxylation of TCAs, possibly leading to unwanted effects. In this
respect, paroxetine, 20 mg/day, under steady-state conditions, was
reported to increase the plasma concentrations of desipramine, a substrate
for CYP2D6, by 327–421% [93,94].
Paroxetine may also impair the elimination of older and newer
antipsychotics, metabolized by CYP2D6. In a pharmacokinetic study in
healthy volunteers, paroxetine was found to cause a two- to 13-fold
increase in single dose perphenazine peak plasma concentrations with
associated CNS effects such as sedation, extrapyramidal symptoms and
impairment of psychomotor performance [95]. In a recent investigation in
schizophrenic patients, paroxetine, 20 mg/day, produced a three- to
nine-fold elevation in plasma levels of risperidone and a minimal but not
significant decrease in the concentrations of the active metabolite,
resulting in a mean 45% increase in plasma concentrations of the active
fraction of risperidone [96]. These changes were associated with
occurrence or worsening of extrapyramidal side effects in some patients.
Some studies have reported that paroxetine may also produce a moderate
elevation in plasma concentrations of clozapine [97,98], but another
investigation has not confirmed this finding [69].
In a study of 20 patients with epilepsy, stabilized on long term
monotherapy with phenytoin, carbamazepine or valproic acid, addition of
19
paroxetine caused no significant changes in plasma concentrations of the
anticonvulsants [99]. A study in healthy subjects showed no increase in
the plasma concentrations of terfenadine, a CYP3A4 substrate, when
coadministered with paroxetine, 20 mg/day, under steady-state conditions
[100].
Although no significant pharmacokinetic interaction between paroxetine
and warfarin has been documented, it has been suggested that bleeding
tendency may increase when the two drugs are coadministered [101].
Caution is therefore advisable when these two drugs are given in
combination.
Sertraline
The major metabolic pathway of sertraline is the N-demethylation to form
N-desmethylsertraline, less potent than parent drug as serotonin reuptake
blocker. CYP3A4 is the major isoform responsible for this reaction but
other isoenzymes including CYP2D6 are probably involved [102]. In
vitro studies have documented that sertraline is mild to moderate inhibitor
of CYP2D6 and a weak inhibitor of the other CYP isoenzymes and this
accounts for its favourable interacation profile [12–14,21–23,103].
Consistent with this biochemical evidence, sertraline appears to have a
favourable drug interaction profile in vivo.
Sertraline, at its usual effective dose of 50 mg/day, was found to cause
modifications in plasma concentrations of TCAs less pronounced as
20
compared with the other SSRIs [94,104]. However, as inhibition of
CYP2D6 is dose-dependent, significant increases in plasma
concentrations of TCAs may occur when higher dosages of sertraline are
administered [105–107].
Two case reports have documented a moderate increase in plasma
concentrations of clozapine after coadministration with sertraline
[108,109]. However, formal kinetic studies have indicated that sertraline
does not affect significantly plasma concentrations of clozapine and
olanzapine [72,97,98].
There is no evidence of a metabolic interaction between sertraline and
benzodiazepines. With regard to this, in healthy volunteers,
coadministration of sertraline, 50–200 mg/day, with diazepam or
alprazolam caused no significant modification in their pharmacokinetic
parameters [110,111]. Two randomized, doubleblind, placebo-controlled
studies in healthy subjects, have indicated that sertraline, at a dose of 200
mg/day, did not alter pharmacokinetic parameters of carbamazepine and
phenytoin, substrates for CYP3A4 and CYP2C9, respectively [112,113].
In another randomized, placebo-controlled trial in healthy volunteers,
sertraline was found to produce a small increase in the free fraction of
warfarin and a modest (8.9%) increase in prothrombin time, which were
considered to be clinically insignificant [114].
Citalopram
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Citalopram is marketed as a racemate, but its pharmacological effects are
almost exclusively ascribed to the S-(+) enantiomer. In this respect,
S-citalopram itself (escitalopram) was recently introduced as an
antidepressant [115]. The main metabolic pathway of citalopram is
N-demethylation to N-desmethylcitalopram, which is further
N-demethylated to didesmethylcitalopram [116]. The major isoenzymes
involved in the metabolism of citalopram are CYP2C19 and CYP2D6:
the N-demethylation of citalopram is mediated by CYP2C19, while
CYP2D6 catalyses the N-demethylation of N-desmethylcitalopram [117].
In vitro studies with human liver microsomes have indicated that
CYP3A4 is also involved in the N-demethylation of citalopram
[118–120]. Citalopram is a weak in vitro inhibitor of CYP2D6 and has
weak or no effects on CYP1A2, CYP2C19 and CYP3A4 [12–14].
Citalopram may be considered the most safe SSRI with respect to
pharmacokinetic drug interactions. In fact, it is neither the cause, nor the
source of clinically important pharmacokinetic drug interactions [121].
In a study in healthy volunteers, concurrent citalopram treatment
increased the area under the plasma concentration/time curve (AUC) of
desipramine by 50% and caused a modest corresponding decrease in the
levels of 2-hydroxydesipramine [122]. This was explained by a weak
inhibitory effect of desmethylcitalopram on CYP2D6, the isoform
responsible for the 2-hydroxylation of desipramine. In the same
22
investigation, the kinetic parameters of imipramine and levomepromazine
were not modified by citalopram. In a case study in five patients, addition
of citalopram did not affect significantly plasma concentrations of some
TCAs such as amitriptyline and clomipramine [123].
Citalopram has been reported not to interfere with the disposition of both
conventional and novel antipsychotics. In a study of 90 schizophrenic
patients citalopram, 40 mg/day, caused no significant changes in plasma
concentrations of haloperidol, chlorpromazine, zuclopenthixol,
levomepromazine, thioridazine or perphenazine [124]. In another
investigation, citalopram, 40 mg/day, had no effect over 8 weeks on
plasma levels of clozapine, risperidone and their active metabolites in 15
patients with chronic schizophrenia [125]. Steady-state plasma
concentration profiles of carbamazepine and its active epoxide metabolite
were not modified during coadministration of therapeutic doses of
citalopram in healthy volunteers [126].
In an open, controlled, randomized, crossover study, coadministration of
citalopram with warfarin produced a small increase in mean prothrombin
time, but this was thought not to be of clinical significance [127].
Other newer antidepressants
The last decade has seen the emergence of a third wave of antidepressant
medications of variable mechanism of action, not confined to serotonin
reuptake inhibition, including venlafaxine, mirtazapine, reboxetine and
23
nefazodone. As with SSRIs, these agents have a wide therapeutic index
and, therefore, the effect of coadministration with inhibitors or inducers
of their metabolism is unlikely to lead to potentially serious consequences.
The inhibitory effect of these antidepressants on various CYP enzymes is
summarized in Table III. With the exception of nefazodone, which
markedly inhibits CYP3A4 activity, they appear to have a relatively low
potential for metabolically based drug interactions.
Venlafaxine
Venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), is
biotransformed in humans to a major active metabolite
O-desmethylvenlafaxine, and in parallel to N-desmethylvenlafaxine. In
vitro and in vivo studies have indicated that the O-demethylation of
venlafaxine is mainly catalysed by CYP2D6, while CYP3A4 is probably
involved in the N-demethylation pathway [128–130]. Different in vitro
studies have demonstrated that venlafaxine is a weak inhibitor of
CYP2D6, considerably less potent than the SSRIs paroxetine, fluoxetine,
fluvoxamine and sertraline [131]. Moreover, this antidepressant does not
affect significantly the activity of CYP1A2, CYP2C9 and CYP3A4
[131,132]. Based on this in vitro evidence, venlafaxine appears to have
have minimal effects on the pharmacokinetics of other drugs in vivo.
Albers et al. [133] evaluated the effect of venlafaxine, 150 mg/day, on the
pharmacokinetics of imipramine in healthy subjects. During venlafaxine
24
treatment, the clearance of imipramine and desipramine was slightly
reduced, leading to a significant increase in their AUC by 27 and 40%,
respectively. In another in vivo investigation, coadministration of
venlafaxine, 150 mg/day, with 1 mg single dose of risperidone, slightly
inhibited its conversion to 9-hydroxyrisperidone (9-OH-risperidone),
which is partially metabolized by CYP2D6 [134]. These findings are
consistent with a statistically significant, but clinically modest impact of
venlafaxine on CYP2D6-metabolized substrates.
Under steady-state conditions venlafaxine, 150 mg/day, did not modify
the single dose pharmacokinetic profiles of drugs metabolized by
CYP3A4, such as diazepam, alprazolam and terfenadine [135–137].
Moreover, it has been reported that plasma concentrations of
carbamazepine and its metabolites are not significantly altered during
coadministration with venlafaxine [138]. Although the precise
mechanism remains uncertain, venlafaxine caused a 70% increase in the
AUC of coadministered haloperidol [139].
Mirtazapine
Mirtazapine is the first of a new class of antidepressants, the
noradrenergic and specific serotonergic antidepressants, whose effect
appears to be related to its dual enhancement of central noradrenergic and
serotonin 5-HT1 receptor-mediated serotonergic neurotransmission.
Mirtazapine is extensively metabolized in the liver and the major
25
metabolic routes are N-demethylation, N-oxidation and 8-hydroxylation.
CYP2D6 and, to a lesser extent, CYP3A4, are involved in the formation
of hydroxymetabolites, CYP3A4 and CYP1A2 catalyse the
N-demethylation, while CYP3A4 is the major isoform involved in the
N-oxidation [140,141]. Based on preclinical studies in human liver
microsomes, mirtazapine has minimal inhibitory effects on CYP1A2,
CYP2D6 and CYP3A4 and, therefore, it is not expected to cause
clinically significant interactions interact with substrates for these
isoforms [140]. The few formal studies available in vivo confirm the
favourable drug interaction profile of mirtazapine.
In a study of psychiatric patients with concomitant psychotic and
depressive symptoms, plasma concentrations of risperidone and its active
9-hydroxy metabolite were not significantly affected by coadministration
of mirtazapine, 30 mg/day [142]. In a pharmacokinetic investigation of
healthy subjects aimed to evaluate the reciprocal interaction between
mirtazapine and carbamazepine, mirtazapine had no effect on
pharmacokinetic parameters of carbamazepine, while carbamazepine
caused a significant decrease in plasma concentrations of the
antidepressant [143].
Reboxetine
Reboxetine is a selective noradrenaline reuptake inhibitor (NaRI), the
first of a new antidepressant class, and it has a low affinity for multiple
26
receptors. Reboxetine has two chiral centres, but only the enantiomeric
pair of (R,R)-())-and (S,S)-(+)- of reboxetine exist in the commercial
product. Reboxetine has a complex hepatic biotransformation in humans
including hydroxylation of the ethoxyphenoxy ring, O-dealkylation, and
oxidation of the morpholine ring, followed by glucoronide- and
sulphoconjugation [144]. In vitro experiments in human liver
preparations have indicated that CYP3A4 is the major enzyme
responsible for the metabolism of each reboxetine enantiomer CYP3A4
[145]. In addition, both reboxetine enantiomers were found to be weak in
vitro inhibitors of the activity of CYP2D6 and CYP3A4, but they had no
effect on the activity of CYP1A2, CYP2C9, and CYP2C19 [145]. The
inhibitory effect of reboxetine on CYP2D6 and CYP3A4 is unlikely to be
relevant in vivo because it occurs at concentrations well above those
achieved clinically. In agreement with this, studies in healthy volunteers
have shown that reboxetine, 8 mg/day, does not interfere with the
pharmacokinetics of dextromethorphan and alprazolam, model substrates
for CYP2D6 and CYP3A4 [144,146]. On account of its weak inhibitory
effect on the hepatic CYP system, reboxetine has a low propensity to
interact with coadministered medications.
Studies in healthy volunteers have indicated that reboxetine does not
affect pharmacokinetic parameters of lorazepam and fluoxetine [147,148].
In a recent study of patients with schizophrenia or schizoaffective
27
disorder with associated depressive symptoms, coadministration of
reboxetine, 8 mg/day, for 4 weeks did not affect plasma concentrations of
clozapine (seven patients), risperidone (seven patients) and their active
metabolites [149].
Nefazodone
Nefazodone is a potent serotonin 5-HT2 receptor antagonist that also
inhibits both serotonin and noradrenaline reuptake. It is extensively
metabolized in the liver by hydroxylation and dealkylation, primarily via
CYP3A4 [150]. Hydroxynefazodone is the major metabolite and displays
pharmacological activity similar to parent drug. Other minor metabolites
include mCPP and a triazoledione derivative which are both less active
than nefazodone. Nefazodone has been shown in vitro to be a potent
inhibitor of CYP3A4 and it has also a weak inhibitory effect on CYP2D6
activity, presumably due to mCPP [151].
The inhibitory effect of nefazodone on CYP3A4 activity has been
demonstrated in several clinical studies in which pharmacokinetic
parameters of known substrates of this isoform were measured in subjects
treated with this antidepressant. In this respect, in healthy volunteers
nefazodone, 200 mg twice daily for 7 days, was found to increase the
plasma concentrations of the triazolobenzodiazepines triazolam and
alprazolam, which are substrates of CYP3A4, by 98 and 290%,
respectively, thereby causing oversedation [152,153]. However, the
28
elimination of lorazepam, a benzodiazepine agent not primarily
metabolized by oxidative processes in the liver, was not affected by
coadministration of nefazodone [154]. In a recent study concomitant
administration of nefazodone with carbamazepine, both substrate and
inducer of CYP3A4, resulted in a small increase in plasma
carbamazepine levels and a marked decrease in plasma concentrations of
nefazodone and its major metabolites [155]. Another in vivo study has
shown a modest 35% increase in plasma concentrations of haloperidol,
whose metabolism involves CYP3A4 and CYP2D6, when coadministered
with nefazodone [156]. The most clinically important drug interactions
with nefazodone may occur when this agent is given in combination with
CYP3A4 substrates with a narrow therapeutic index. In this respect, case
reports have documented the occurrence of nephro- and neurotoxicity
when nefazodone was associated with the immunosuppressant agents
cyclosporin or tacrolimus [157–159], and myositis and rhabdomyolysis
with simvastatin [160,161]. Moreover, concomitant use of nefazodone
with certain CYP3A4 substrates including cisapride, astemizole,
terfenadine or loratadine, is contraindicated as it may predispose to
‘torsades de pointes’, a potentially fatal ventricular dysrhythmias
associated with marked electrocardiographic QTc prolongation [162,163].
METABOLIC DRUG INTERACTIONS WITH NEW
ANTIPSYCHOTICS
29
The advent of the newer antipsychotics, the so-called ‘atypical
antipsychotics’, has had a major impact upon the treatment of
schizophrenia and related psychotic disorders. As compared with
traditional antipsychotics, newer compounds are characterized by a lower
potential to induce extrapyramidal symptoms and elevate serum prolactin
levels, and by beneficial effects on positive and negative symptoms and,
possibly, other symptom dimensions in schizophrenia (i.e. cognitive,
aggressive and depressive symptoms) [164,165]. The novel
antipsychotics currently available include clozapine, risperidone,
olanzapine, quetiapine, ziprasidone and amisulpride. Another new agent,
sertindole, has been withdrawn from the market because of prolongation
of the QTc interval on ECG with subsequent risk of ventricular
dysrhythmias and sudden deaths. The relevant characteristics of newer
antipsychotics for metabolic pharmacokinetic interactions are
summarized in Table IV. A major advantage of novel antipsychotics over
classical compounds in terms of potential for drug interactions is
represented by their negligible effect on hepatic drugmetabolizing
enzymes. Differently from some older antipsychotics, namely
phenothiazines, which are potent inhibitors of CYP2D6 and may
therefore impair the elimination of substrates for this isoform [166], novel
antipsychotics are only weak in vitro inhibitors of CYP isoenzymes at
therapeutic concentrations [167,168]. Therefore, these compounds are not
30
expected to interfere with the elimination of any coadministered
medication medication. On the contrary, concomitant administration of
inhibitors or inducers of the major CYPs involved in the metabolism of
novel antipsychotics may increase or decrease their plasma
concentrations, possibly leading to adverse effects or decreased efficacy
[169–172] (Table V).
Clozapine
Clozapine is a dibenzodiazepine derivative, recognized as the prototypic
novel antipsychotic. Clozapine has a complex hepatic metabolism in
humans: the major metabolic pathways are the N-demethylation and the
N-oxidation to form N-desmethylclozapine, which has limited
pharmacological activity, and clozapine N-oxide, respectively. In vivo
and in vitro studies suggest that multiple CYP isoforms are involved in
the biotransformation of clozapine [173,174]. The N-demethylation
appears to be mediated by CYP1A2 and, to a lesser extent, by CYP3A4.
There is evidence that also CYP2D6 and CYP2C19 contribute to this
reaction. The N-oxidation is predominantly catalysed by CYP3A4. Minor
metabolic routes of clozapine biotransformation include 8-hydroxylation
and direct N-glucuronidation. Concomitant administration of compounds,
acting as inhibitors or inducers of CYP enzymes involved in clozapine
metabolism, may therefore affect plasma clozapine concentrations with
potential clinical implications [175,176]. In this respect, it must be
31
underlined that clozapine CNS toxicity (e.g. generalized seizures,
confusion, delirium) occurs more frequently at plasma concentrations
above 1000 ng/mL [177].
As already mentioned, clinically relevant drug interactions may occur
between SSRIs and clozapine. In particular fluvoxamine, a potent
inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP3A4,
has been reported to cause a five- to 10-fold elevation of plasma
clozapine concentrations, possibly associated with signs of toxicity
[66–69]. Fluoxetine and paroxetine may also increase plasma clozapine
concentrations, while sertraline and citalopram have been reported to
cause minimal or no elevation of plasma levels of this antipsychotic
[33,34,97,98,125]. Based on this evidence, careful clinical observation
and monitoring of serum clozapine levels are recommended whenever
SSRIs are added to patients chronically treated with clozapine.
The potential interaction between clozapine and caffeine, a substrate of
CYP1A2, was first documented by Vainer and Chouinard [178] who
described a patient with schizophrenia experiencing short-lasting acute
psychotic exacerbation each time he was receiving clozapine with coffee.
These reactions did not occur when clozapine was taken with water.
Apart from the possibility of a pharmacodynamic interaction, this effect
might be due to a competitive pharmacokinetic interaction between
clozapine and caffeine at the CYP1A2 enzyme level resulting in an
32
increased concentration of one or both drugs. Consistent with this, and a
controlled study in patients with schizophrenia documented a decrease by
about 50% in plasma clozapine concentrations after caffeine withdrawal
from the diet [179].
In a formal pharmacokinetic study in patients with schizophrenia,
coadministration of low doses of ciprofloxacin (250 mg twice daily), a
potent inhibitor of CYP1A2, resulted in a moderate elevation (by 29%) of
serum concentrations of clozapine and norclozapine [180].
Controversial findings have been reported concerning the interaction
between erythromycin, a macrolide antibiotic with a strong inhibitory
effect on CYP3A4, and clozapine. Case reports have indicated that
concomitant treatment with erythromycin resulted in an elevation of
plasma clozapine levels, along with toxic effects [181,182]. Conversely,
in a study in healthy subjects, no modifications in the disposition of
clozapine during coadministration with erythromycin, suggesting a
limited involvement of CYP3A4 in the metabolism of clozapine in
humans [183]. In agreement with this, two other potent inhibitors of
CYP3A4, the azole antimycotic itraconazole and the new antidepressant
nefazodone, were found not to affect plasma concentrations of clozapine
and norclozapine in schizophrenic patients [184,185].
Several studies indicate that plasma concentrations of clozapine and
norclozapine are generally lower in smokers compared with nonsmokers,
33
especially in male subjects [186]. This effect is probably explained by the
inducing effect of cigarette smoking on CYP1A2 activity.
Discontinuation of tobacco smoke in patients stabilized on clozapine
would potentially lead to increased plasma clozapine concentrations and
subsequent risk of unwanted effects.
Enzyme-inducing anticonvulsants such as carbamazepine, phenytoin and
phenobarbital may decrease the plasma concentration of clozapine,
presumably by induction of CYP1A2 and CYP3A4 [187–190]. With
regard to the interaction between carbamazepine and clozapine, such a
combination should be avoided as a result of concerns about potential
additive adverse haematological effects [191]. There is conflicing
evidence concerning the effect of valproic acid on clozapine metabolism.
In fact, plasma concentrations of clozapine and its metabolites have been
reported to be either decreased or increased slightly after the addition of
valproic acid [33,192–194].
Risperidone
Risperidone, a benzisoxazole derivative, is primarily metabolized by
9-hydroxylation, while 7-hydroxylation and oxidative N-dealkylation are
quantitativly less important routes of biotransformation. The metabolism
of risperidone to 9-OH-risperidone is mediated by CYP2D6 [195,196]. In
vitro studies by using recombinant CYP enzymes and human liver
metabolites have confirmed that CYP2D6 is the major isoform involved
34
in the formation of 9-OH-risperidone, but have also suggested an
involvement of CYP3A4 [197,198]. As this metabolite is claimed to be
equipotent with the parent drug in terms dopamine-receptor affinity, the
sum of plasma concentrations of parent drug and metabolite is often
referred to as the ‘active moiety’. Concomitant treatment with drugs that
inhibit CYP2D6 (no inducers are known) and inhibit or induce CYP3A4
could potentially modify the plasma concentrations of risperidone,
9-OH-risperidone, or both through metabolic drug interactions [199]. In
this respect, it was believed that coadministration of drugs interfering
with CYP enzymes might affect the ratio between risperidone and its
metabolite, but should not modify the active fraction of risperidone, with
no major clinical consequences [171]. However, recent studies have
demonstrated that addition of inhibitors of CYP2D6 or inducers of
CYP3A4 may cause a significant change in total plasma risperidone
concentrations, eventually associated with clinically relevant effects.
With regard to this, the occurrence of extrapyramidal side effects in
patients treated with risperidone was found to be correlated with plasma
levels of its active moiety [200].
As already mentioned, formal kinetic studies in patients with
schizophrenia have demonstrated that concomitant treatment with
fluoxetine and paroxetine, potent inhibitors of CYP2D6, may cause a
significant elevation in the plasma concentrations of risperidone and in its
35
active fraction of risperidone (without affecting significantly levels of the
9-OH-metabolite), with possible occurrence or worsening of
extrapyramidal symptoms [35,36,96]. To explain the increase in total
plasma risperidone concentrations during combined treatment with
paroxetine and fluoxetine, it can be speculated that these two SSRIs also
inhibit the further biotransformation of 9-OH-risperidone and/or affect
alternative routes of risperidone metabolism. It might be appropriate to
reduce risperidone dose to prevent this interaction. Unlike fluoxetine and
paroxetine, other antidepressants with a weaker inhibitory effect on
CYP2D6, including amitriptyline, citalopram, venlafaxine, mirtazapine
and reboxetine reboxetine were found not to modify significantly total
plasma risperidone concentrations [125,134,142,149,201].
Unusually high active moiety concentrations of risperidone were
described in a patient receiving concomitant treatment with nefazodone, a
substantial CYP3A4 inhibitor [202]. Although there are no reports on the
effects of other CYP3A4 inhibitors such as ketoconazole or erythromycin
on risperidone disposition, caution should be exercised if they are added
to an existing risperidone treatment.
Carbamazepine, an inducer of drug-metabolizing enzymes, has been
reported to decrease plasma concentrations of risperidone,
9-OH-risperidone and the active moiety by approximately 50, 80 and
65%, respectively, in subjects receiving risperidone and carbamazepine
36
compared with those treated with risperidone alone or in combination
with valproate [203,204]. The clinical relevance of this interaction was
documented in a case study, concerning a patient with chronic
schizophrenia in whom addition of carbamazepine to pre-existing
risperidone therapy resulted in a marked decrease in the plasma
concentrations of both risperidone and its 9-hydroxy-metabolite and in an
acute exacerbation of psychotic symptoms [205]. This interaction may be
attributed to the inducing effect of carbamazepine on CYP3A4-mediated
metabolism of risperidone. Up to date, there are no reports on the effect
of other CYP3A4 inducers, such as rifampin, phenytoin and
Phenobarbital on risperidone disposition.
Olanzapine
Olanzapine is a thienobenzodiazepine derivative structurally related to
clozapine. Its major metabolic pathways include direct N-glucuronidation,
mediated by uridine diphosphate glucuronyltransferase (UDPGT), and
N-demethylation, mediated by CYP1A2 [206]. Minor pathways include
N-oxidation, catalysed by flavincontaining mono-oxygenase-3 system,
and 2-hydroxylation, metabolized by CYP2D6. As CYP1A2 and, to a
lesser extent, CYP2D6 are responsible for the formation of oxidative
metabolites of olanzapine, coadministration of other drugs that affect
these isoenzymes may influence the elimination of olanzapine. However,
as the risk of clinically relevant drug–drug interactions at CYP system
37
level appears to be relatively low, being olanzapine principally
metabolized by direct N-glucuronidation.
Coadministration of potent inhibitors of CYP1A2, such as fluvoxamine
and ciprofloxacin, has been reported to cause significant changes in
olanzapine pharmacokinetics. The occurrence of a clinically rele-vant
metabolic interaction between fluvoxamine and olanzapine has been
already mentioned [72–74]. In a patient stabilized on olanzapine therapy,
addition of ciprofloxacin 250 mg twice daily, almost doubled the plasma
antipsychotic concentrations, suggesting the possibility of a metabolic
interaction between these two drugs [207].
However, inducers of CYP1A2, such as cigarette smoking and
carbamazepine, may accelerate the metabolism of olanzapine. Consistent
with this, it is known that smoking may increase the clearance of
olanzapine and reduce its plasma half-life by as much as 40% [208]. In a
formal pharmacokinetic study of healthy subjects, administration of
carbamazepine, 200 mg twice daily for 2 weeks, resulted in a significant
decrease in mean peak plasma concentrations (Cmax), AUC, and half-life
of olanzapine, by 24, 33 and 20%, respectively, while its plasma
clearance increased by 46% [209]. Moreover, in two studies of
psychiatric patients receiving olanzapine, subjects co-medicated with
carbamazepine had plasma olanzapine concentrations approximately
30–50% lower compared with patients on olanzapine monotherapy
38
[210,211]. Induction of CYP1A2 and, possibly, UDPGT by
carbamazepine is the more likely mechanism of this interaction. In a
recent pharmacokinetic investigation in healthy volunteers, concomitant
administration of ritonavir, a HIV-1 protease inhibitor known to inhibit
CYP3A4 and to induce CYP1A2 and UDPGT, at a dose of 300–500 mg
twice daily, caused changes in olanzapine AUC ()53%) and and clearance
(+115%) greater as compared with cigarette smoking and carbamazepine
[212].
Concurrent use of olanzapine with inhibitors of CYP2D6 may
theoretically lead to interactions, perhaps by affecting the minor
metabolic pathway forming 2-hydroxymethyl olanzapine. In a recent
pharmacokinetic study of healthy volunteers, coadministration of
fluoxetine, 60 mg/day, caused only slight and probably clinically
insignificant modifications in pharmacokinetic parameters of a single 5
mg dose of olanzapine [213].
Quetiapine
Quetiapine, a dibenzothiazepine derivative, is extensively metabolized in
the liver by sulphoxidation to form its major, but inactive, sulphoxide
metabolite, and, as lesser metabolic pathways, by N- and O-dealkylation.
CPY 3A4 appears to be the major isoenzyme involved in these metabolic
reactions [169]. Therefore, drugs that affect the activity of CYP3A4 may
interfere with the disposition of quetiapine.
39
In a multiple-dose trial in 12 healthy subjects, concomitant treatment with
ketoconazole, a potent inhibitor of CYP3A4, increased Cmax and AUC
for quetiapine by 235 and 522%, respectively, and decreased of its
plasma clearance by 84% [214]. Reduced doses of quetiapine may be
required during co-administration with potent CYP3A4 inhibitors, such
as azole antifungals and macrolide antibiotics.
Inducers of CYP3A4, such as phenytoin, carbamazepine, barbiturates and
rifampin, may accelerate the metabolism of quetiapine, decreasing its
plasma concentrations and potentially leading to reduced efficacy. In this
respect, in a pharmacokinetic study in psychiatric patients, concomitant
phenytoin administration caused a marked decrease in plasma quetiapine
levels, resulting in a fivefold increase in its apparent oral clearance [215].
Based on this evidence, the dosage of quetiapine should be increased to
maintain a therapeutic effect if this agent is used concomitantly with
hepatic inducers.
Concomitant treatment with inhibitors of other CYP enzymes is not
expected to alter significantly quetiapine pharmacokinetics. Consitent
with this, in a recent investigation in healthy volunteers, imipramine, a
CYP2D6 substrate, had no significant effect on the pharmacokinetics of
quetiapine, while fluoxetine, a potent CYP2D6 inhibitor and a moderate
CYP3A4 inhibitor, caused a minimal, not statistically significant increase
in the AUC (by 12%) and Cmax (by 26%) of the antipsychotic [216]. In a
40
pharmacokinetic study involving 13 psychotic patients, concomitant
administration of cimetidine, a potent nonspecific inhibitor of the CYP
system, produced minimimal, not statistically significant changes in the
pharmacokinetics of quetiapine [217].
Ziprasidone
Ziprasidone is a novel antipsychotic marketed in the US and in some
European countries. It has a complex metabolism and the major pathways
include oxidation at sulphur resulting in the formation of
ziprasidone–sulphoxide and ziprasidone–sulphone and N-dealkylation
[218]. CYP3A4 has been identified as the primary isoenzyme involved in
the metabolism of ziprasidone. Few formal studies have evaluated the
drug interaction profile of ziprasidone. As with quetiapine, concomitant
administration of CYP3A4 inhibitors or inducers is expected to result in
increased or decreased plasma ziprasidone concentrations, respectively.
In a pharmacokinetic investigation in healthy volunteers,
coadministration of ketoconazole, a potent inhibitor of CYP3A4, caused a
modest, statistically significant increase in ziprasidone Cmax and AUC,
by 34 and 33%, respectively [219]. Conversely, concomitant treatment
with carbamazepine, an inducer of CYP3A4, was associated with a mean
27% decrease in ziprasidone Cmax and a 36% reduction in its AUC [220].
In both of these studies, changes in the pharmacokinetics of ziprasidone
were considered unlikely to be clinically relevant, in view of the broad
41
therapeutic index of ziprasidone and magnitude of the interaction,.
However, as ziprasidone is associated with slight prolongation of the QTc
interval, caution may be required when it is coadministered with potent
CYP3A4 inhibitors.
Amisulpride
Amisulpride, a substituted benzamide derivative, is a novel antipsychotic
that antagonizes postsynaptic dopamine D2 and D3 receptors,
preferentially in the limbic system rather than the striatum. Amisulpride
is primarily excreted in the urine and undergoes relatively little
metabolism. Its biotransformation in humans includes N-dealkylation and
oxidation, but the isoenzymes involved in these reactions are yet
unidentified [221]. As a consequence of its limited metabolic elimination,
amisulpride is unlikely to be involved in clinically relevant
pharmacokinetic drug interactions.
CONCLUSIONS
New psychotropic drugs may be subject to metabolically based drug
interactions at level of the hepatic CYP system. Some of these
interactions are well documented and may be clinically relevant, while
others have been reported only anecdotally or reflect pharmacokinetic
observations of doubtful practical importance. Moreover, the drug
interaction profile of new psychoactive agents is only partially known, in
particular, for those compounds more recently marketed.
42
New antidepressants are not equivalent in their potential for metabolic
drug interactions. Fluoxetine and paroxetine are potent inhibitors of
CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while
nefazodone is a potent inhibitor of CYP3A4. Therefore, clinically
relevant interactions are expected when these agents are coadministered
with substrates of these isoforms, especially those with a narrow
therapeutic index. Other new antidepressants including sertraline,
citalopram, venlafaxine, mirtazapine and reboxetine possess a weak
inhibitory effect on different CYP isoforms in vitro and appear to have a
more favourable drug interaction profile also in vivo.
The new atypical antipsychotics are weak inhibitors of CYP isoenzymes
and therefore may only have negligible effects on the elimination of other
medications concomitantly administered. On the contrary, drugs which
inhibit or induce the CYP isoenzymes involved in metabolism of the
various antipsychotic compounds may alter their plasma concentrations
with subsequent risk of adverse effects or decreased efficacy. The clinical
significance of these interactions should be interpreted in relation to the
relatively wide therapeutic index of these compounds.
Information on CYP isoenzymes involved in the metabolism of new
psychotropic agents and knowledge of their effects on the activity of
these enzymes may help clinicians to predict and eventually avoid certain
drug combinations. Moreover, potentially adverse drug interactions may
43
be anticipated and minimized by appropriate dosage adjustments based
on close evaluation of clinical effects and, possibly, plasma drug
concentration monitoring.
In addition to the introduction of new psychotropic drugs, in recent years
herbal therapies have become a popular form of alternative or
complementary treatment of several psychiatric symptoms, including
depression, anxiety and insomnia. In general, herbal medicines are
advertized as being safe and natural. However, their active ingredients
have pharmacological properties and the potential for drug interactions
may be underestimated [222,223]. In this respect, St John’s wort
(Hypericum perforatum) is increasingly used to treat mild to moderate
depression [224]. Numerous reports indicate the possibility of important
interactions, particularly with drugs metabolized by the CYP system. St
John’s wort constituents may induce CYP3A4, and possibly other CYPs,
and may cause a remarkable decrease in plasma concentrations of several
drugs including cyclosporin, warfarin, theophylline, digoxin, oral
contraceptives, indinavir and amitriptyline [223].
44