Inhibition of CYP2D6 Activity by Bupropion

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Twin Cities Campus, Minneapolis, MN 55455, USA.
Journal of Clinical Psychopharmacology (Impact Factor: 3.24). 07/2005; 25(3):226-9. DOI: 10.1097/
Source: PubMed


The purpose of this study was to assess the effect of bupropion on cytochrome P450 2D6 (CYP2D6) activity. Twenty-one subjects completed this repeated-measures study in which dextromethorphan (30-mg oral dose) was administered to smokers at baseline and after 17 days of treatment with either bupropion sustained-release (150 mg twice daily) or matching placebo. Subjects quit smoking 3 days before the second dextromethorphan administration. To assess CYP2D6 activity, urinary dextromethorphan/dextrorphan metabolic ratios were calculated after an 8-hour urine collection. Thirteen subjects received bupropion, and 8 received placebo. In those receiving active medication, the dextromethorphan/dextrorphan ratio increased significantly at the second assessment relative to the first (0.012 +/- 0.012 vs. 0.418 +/- 0.302; P < 0.0004). No such change was observed in those randomized to placebo (0.009 +/- 0.010 vs. 0.017 +/- 0.015; P = NS). At baseline, all subjects were phenotypically extensive CYP2D6 metabolizers (metabolic ratio <0.3); after treatment, 6 of 13 subjects receiving bupropion, but none of those receiving placebo, had metabolic ratios consistent with poor CYP2D6 metabolizers. Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6.

Download full-text


Available from: David Adson, Oct 20, 2015
  • Source
    • "Bupropion, and particularly erythro-hydrobuprion and threohydrobupropion have previously been shown to inhibit CYP2D6 (Jefferson et al., 2005; Kotlyar et al., 2005; Reese TABLE 3 Pharmacokinetic parameters of MDMA and bupropion and metabolites Values are mean 6 S.E.M. in 16 healthy subjects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular recreational drug. The study aim was to explore the role of dopamine in the psychotropic effects of MDMA using bupropion to inhibit the dopamine and norepinephrine transporters through which MDMA releases dopamine and norepinephrine. The present study investigated the pharmacodynamic and pharmacokinetic interactions between bupropion and MDMA in 16 healthy subjects using a double-blind, placebo-controlled, crossover design. Bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA. In contrast, bupropion increased plasma MDMA concentrations and prolonged its subjective effects. Conversely, MDMA increased plasma bupropion concentrations. The results indicate a role for the transporter-mediated release of norepinephrine in the cardiostimulant effects of MDMA but do not support a modulatory role for dopamine in the mood effects of MDMA. These results also indicate that the use of MDMA during therapy with bupropion may result in higher plasma concentrations of both MDMA and bupropion and enhanced mood effects but lower cardiac stimulation. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Feb 2015 · Journal of Pharmacology and Experimental Therapeutics
  • Source
    • "Bupropion acts predominantly on 2D6 and has no action on 2C9.[22] This makes the bupropion-warfarin interaction, in this case, difficult to explain in the light of available evidence. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Depressive illness and thromboembolic disorders are both highly prevalent. Warfarin is frequently combined with an antidepressant drug, the choice of which depends mainly on the risk of a hemorrhagic complication. Patients requiring the warfarin are often in the older age group, where the newer antidepressants with a better safety profile are preferred over tricyclic antidepressants. We report herein, a patient who was on bupropion for depression, when he developed deep vein thrombosis high-risk. Warfarin was started. While on this combination bupropion was abruptly stopped. This caused a more than two-fold elevation of international normalized ratio (INR) above the level, which is considered a high-risk for a hemorrhagic complication. INR reverted back to the desired level on reintroduction of bupropion. This indicates that a bupropion-warfarin combination should be used with the caution, though there has been no reported interaction so far.
    Full-text · Article · Jul 2013 · Indian Journal of Psychological Medicine
  • Source
    • "Although bupropion is not significantly cleared by CYP2D6, it has been described as a potent inhibitor of this important xenobiotic metabolizing enzyme in vivo (Kotlyar et al. 2005). Bupropion has been shown to alter the clinical PK of CYP2D6 substrates, including dextromethorphan (Kotlyar et al. 2005), nortriptyline (Weintraub 2001), metoprolol (McCollum et al. 2004), venlafaxine (Kennedy et al. 2002) and desipramine (Jefferson et al. 2005; Reese et al. 2008). Further in vitro mechanistic studies demonstrated that neither bupropion nor hydroxybupropion are significant inhibitors of CYP2D6, rather the reductive metabolites are potent competitive inhibitors of CYP2D6 (Reese et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bupropion is metabolized extensively in humans by oxidative and reductive processes. CYP2B6 mediates oxidation of bupropion to hydroxybupropion, but the enzyme(s) catalyzing carbonyl reduction of bupropion to erythro- and threohydrobupropion in human liver is unknown. The objective of this study was to examine the enzyme kinetics of bupropion reduction in human liver. In human liver cytosol, the reduction of bupropion to erythro-and threohydrobupropion was NADPH dependent with Cl(int) values of 0.08 and 0.60 µL·min(-1)mg(-1) protein, respectively. Bupropion reduction in liver microsomes was also NADPH dependent with Cl(int) values of 10.4 and 280 µL·min(-1)mg(-1) protein, respectively. Formation of erythro-and threohydrobupropion in microsomes exceeded that in cytosol by 70 and 170 fold, respectively. Menadione, an inhibitor of cytosolic carbonyl reducing enzymes (e.g. CBRs), inhibited erythro-and threohydrobupropion formation in cytosol with IC(50) of 30 and 54 µM, respectively. In microsomes 18β-glycyrrhetinic acid, an inhibitor of microsomal carbonyl reductases (e.g. 11β-HSDs), inhibited their formation with IC(50) of 25 and 26 nM, respectively. Our findings, in agreement with recent human placental studies, show that carbonyl reducing enzymes in hepatic microsomes are significant players in bupropion reduction. Contrary to past studies, we found that threohydrobupropion (not hydroxybupropion) is the major microsomal generated hepatic metabolite of bupropion.
    Full-text · Article · Feb 2012 · Xenobiotica
Show more