Effect of venlafaxine on imipramine metabolism
Introduction
Advances in psychopharmacology have led to the development of antidepressants like the selective serotonin reuptake inhibitors (SSRIs) that are highly specific for different neurotransmitters. These drugs have a more benign side-effect profile than tricyclic antidepressants (TCAs) and are much less toxic in overdose. Given the numerous new-generation antidepressants available, it is important to find agents that offer the greatest benefit with the smallest number of side effects or drug–drug interactions.
Venlafaxine and its major active metabolite O-desmethylvenlafaxine (ODV) are potent inhibitors of both serotonin and norepinephrine uptake (Montgomery, 1993). Venlafaxine has no significant effect on muscarinic, alpha-adrenergic or histaminic receptors in vitro (Montgomery, 1993). Venlafaxine and ODV are only weak inhibitors of dopamine reuptake and have no effect on monoamine oxidase inhibition. Both inpatient and outpatient depression studies show that venlafaxine is effective and well tolerated (Ballenger, 1996).
Although single drug therapy for depression is preferable, approximately 30% of patients are treatment-resistant to monotherapy. Effective strategies for treatment-resistant depression include lithium or triiodothyronine augmentation. New-generation antidepressants such as fluoxetine have been added to TCA non-responders, thereby converting them to responders (Weilburg et al., 1989).
The primary concern when combining these agents with TCAs is the potential inhibition of metabolism, which may lead to toxic levels of TCAs and life-threatening sequelae. The mechanism of these drug interactions is partly due to competitive inhibition of TCA metabolism at cytochrome P450 isoenzymes. Metabolism of tertiary amines such as imipramine begins with demethylation to secondary amines after which the tricyclic nucleus is oxidized by hepatic microsomal enzymes and then conjugated with glucuronic acid and excreted. CYP1A2 and CYP3A4 appear to be the primary enzymes involved in the N-demethylation of imipramine to desipramine (Lemoine et al., 1993), but CYP2C19, mephenytoin hydroxlase, may also be involved (Skjelbo et al., 1991). The hydroxylation of imipramine and desipramine to 2-OH-imipramine and 2-OH-desipramine is catalyzed primarily by CYP2D6 (Brosen et al., 1991).
Several in vivo studies have characterized these drug–drug interactions. A detailed analysis of the interaction between fluoxetine and tricyclic metabolism demonstrates up to a 10-fold reduction in oral clearance of imipramine and desipramine and as much as a fourfold prolongation of TCA half-life when fluoxetine is added (Bergstrom et al., 1992). Paroxetine has also been shown to inhibit the metabolism of desipramine as evidenced by a twofold increase in Cmax, a threefold prolongation of half-life, a fivefold decrease in total clearance, and a 10-fold decrease in clearance by 2-hydroxylation (Brosen et al., 1993). Citalopram produced a 47% increase in the AVC of desipramine (Gram et al., 1993). The addition of sertraline to desipramine has been shown to increase desipramine Cmax and AUC by 31% and 23%, respectively (Preskorn et al., 1994). Sertraline has also been noted to have a modest inhibition of CYP2D6 activity in vivo as measured by the log O-demethylation ratio of dextromethorphan (Ozdemir et al., 1998). Fluvoxamine does not significantly alter the pharmacokinetics of desipramine, but does markedly increase imipramine plasma concentrations and half-life, and decrease clearance, consistent with inhibition of CYP1A2 (Spina et al., 1993).
In vitro studies indicate that venlafaxine has less inhibition of CYP2D6 than paroxetine, fluoxetine, norfluoxetine, fluvoxamine or sertraline (Otton et al., 1994, Otton et al., 1996, Ball et al., 1997). Other in vitro data have shown minimal to non-existent inhibition of CYP3A4, CYP1A2 or CYP2C9 with venlafaxine (Ball et al., 1996, Von Moltke et al., 1997).
The in vivo studies with venlafaxine support the favorable in vitro data. Venlafaxine has no clinically significant change in the pharmacokinetics of the CYP2C19 substrate diazepam in vivo (Troy et al., 1995a). Other in vivo studies show no significant effect on the metabolism of the CYP3A4 substrates, carbamazepine (Wiklander et al., 1995) terfenadine (Amchin et al., 1997a, Amchin et al., 1998b), and alprazolam (Amchin et al., 1998a). Venlafaxine has no significant impact on the CYP1A2-mediated metabolism of caffeine in vivo (Amchin et al., 1997b, Amchin et al., 1999). Venlafaxine produces only modest inhibition of the CYP2D6 substrate dextromethorphan in vivo (Amchin et al., 1996, Lam et al., 1997). Ereshefsky (1996) compared the effect of venlafaxine vs. fluoxetine on the metabolism of dextromethorphan. Venlafaxine increased the dextromethorphan-to-dextrorphan ratio 1.95 times compared to 17.11 times for fluoxetine, thus supporting other data that venlafaxine inhibits CYP2D6 significantly less than fluoxetine. Wyeth-Ayerst Laboratories performed studies to determine the effect of venlafaxine on imipramine and desipramine; however, the data have not been published and the results are available only in the Physicians Desk Reference (PDR, 2000). The PDR indicates that venlafaxine has no effect on the metabolism of imipramine but increases desipramine AUC, Cmax, and Cmin by approximately 35%. Imipramine did not affect the pharmacokinetics of venlafaxine or ODV. Further data from the PDR indicate that steady-state venlafaxine at 75 mg every 12 h inhibits the CYP2D6-mediated metabolism of risperidone to its active metabolite, 9-hydroxyrisperidone, leading to a 32% increase in risperidone AUC. This metabolic inhibition did not lead to an alteration in the pharmacokinetic profile of the total active moiety of risperidone+9-hydroxyrisperidone. Taken together, the in vitro and in vivo data support modest inhibition of CYP2D6-mediated metabolism by venlafaxine. This study was designed to determine the in vivo effect of venlafaxine on imipramine metabolism in an attempt to further elucidate the potential for cytochrome P450 drug–drug interactions with venlafaxine.
Section snippets
Subjects
Eight male veterans participated as inpatients in the study after informed consent was obtained. Initially, seven Caucasian subjects and one African-American subject were enrolled. Two subjects were excluded after completing the protocol as they were poor metabolizers of dextromethorphan. This left six subjects, who ranged in age from 23 to 64 years (mean=45.3±15 years). The six remaining subjects comprised five Caucasians and one African-American. Subjects were excluded if they had a history
Adverse reactions
All enrolled subjects completed the protocol. The most common side effect of venlafaxine was mild nausea, which resolved after the initial doses. No patient experienced severe nausea or emesis, and no significant changes in blood pressure were observed. With imipramine, several subjects had mild to moderate sedation along with anticholinergic side effects that were not subjectively potentiated by the addition of venlafaxine.
CYP2D6 phenotype
Dextromethorphan log metabolic ratios were as follows for the eight
Discussion
Venlafaxine had a minimal effect on pharmacokinetic parameters after a single dose of imipramine. The 28% increase in imipramine Cmax and AUC was less than that seen with fluoxetine (Bergstrom et al., 1992) or paroxetine (Brosen et al., 1993, Albers et al., 1996). The elevation of Cmax approached but did not reach statistical significance. The effect on imipramine pharmacokinetic parameters may be underestimated to some degree due to lower than expected plasma venlafaxine levels and single dose
Acknowledgements
The research reported was supported in part by an educational grant from Wyeth-Ayerst, NARSAD (CR), MH 00534 (RP), and MH 47193 (RP).
References (37)
- et al.
Paroxetine shifts imipramine metabolism
Psychiatry Research
(1996) - et al.
Venlafaxine and metabolites are very weak inhibitors of human cytochrome P450-3A isoforms
Biological Psychiatry
(1997) - et al.
Evaluation of the potential pharmacokinetic interaction of venlafaxine and carbamazepine [abstract]
European NeuroPsychopharmacology
(1995) - Amchin, J.D., Ereshefsky, L., Zarycranski, W.M., 1996. Effect of venlafaxine versus fluoxetine on the metabolism of...
- et al.
Venlafaxine's lack of CYP3A4 inhibition addressed by terfenadine metabolism
Clinical Pharmacology and Therapeutics
(1997) - et al.
Evidence that venlafaxine does not inhibit CYP1A2 as measured in vivo by the metabolism of caffeine
Clinical Pharmacology and Therapeutics
(1997) - et al.
Effect of venlafaxine on the pharmacokinetics of alprazolam
Psychopharmacology Bulletin
(1998) - et al.
Effect of venlafaxine on the pharmacokinetics of terfenadine
Psychopharmacology Bulletin
(1998) - et al.
Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine
Journal of Clinical Pharmacology
(1999) - et al.
Venlafaxine (VF): effects on CYP2D6 dependent imipramine and desipramine (DMI) 2-hydroxylation; comparative studies with fluoxetine (Flu) and effects on CYP1A2, CYP3A4 and CYP2C9
Clinical Pharmacology and Therapeutics
(1996)
Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2
British Journal of Clinical Pharmacology
Clinical evaluation of venlafaxine
Journal of Clinical Psychopharmacology
Quantification and mechanism of fluoxetine and tricyclic antidepressant interaction
Clinical Pharmacology and Therapeutics
Role of P450IID6, the target of the sparteine-debrisoquine oxidation polymorphism in the metabolism of imipramine
Clinical Pharmacology and Therapeutics
Fluoxetine and norfluoxetine are potent inhibitors of P450IID6 — the source of the sparteine/debrisoquine oxidation polymorphism
British Journal of Clinical Pharmacology
Inhibition by paroxetine of desipramine metabolism in extensive but not poor metabolizers of sparteine
European Journal of Clinical Pharmacology
Stimultaneous determination of dextromethorphan and three metabolites in plasma using high-performance liquid chromatography with application to their disposition in man
Therapeutic Drug Monitoring
Drug–drug interactions involving antidepressants: focus on venlafaxine
Journal of Clinical Psychopharmacology
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