Inhibition of CYP2D6 Activity by Bupropion

Kotlyar, Michael; Brauer, Lisa H.; Tracy, Timothy S.; Hatsukami, Dorothy K.; Harris, Jennifer; Bronars, Carrie; Adson, David E.

doi:10.1097/01.jcp.0000162805.46453.e3

Cited by 117 publications

(85 citation statements)

References 24 publications

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“…The mechanism for CYP2D6 inhibition best fit a competitive model. It has been suggested that the clinical drug-drug interaction with bupropion and CYP2D6 substrates may be the result of mechanism-based CYP2D6 inhibition by bupropion (Kotlyar et al, 2005). Our investigations showed that neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors (data not shown).…”

Section: Resultsmentioning

confidence: 71%

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An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction

Reese

Wurm²,

Muir³

et al. 2008

Drug Metab Dispos

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ABSTRACT:There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolized drug desipramine resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in bupropion clearance, and bupropion and its major active metabolite, hydroxybupropion, are not strong CYP2D6 inhibitors in vitro. The aims of this study were to investigate whether bupropion's reductive metabolites, threohydrobupropion and erythrohydrobupropion, contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, erythrohydrobupropion and threohydrobupropion were more potent inhibitors of CYP2D6 activity (K i ‫؍‬ 1.7 and 5.4 M, respectively) than hydroxybupropion (K i ‫؍‬ 13 M) or bupropion (K i ‫؍‬ 21 M). Furthermore, neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors. Using the in vitro kinetic constants and estimated liver concentrations of bupropion and its metabolites, modeling was able to predict within 2-fold the increase in desipramine exposure observed when coadministered with bupropion. This work indicates that the reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo and provides a mechanistic explanation for the clinical drug-drug interaction between bupropion and desipramine.Bupropion is a norepinephrine/dopamine reuptake inhibitor currently indicated for the treatment of major depressive disorder (Wellbutrin; GlaxoSmithKline, Research Triangle Park, NC) and smoking cessation (Zyban; GlaxoSmithKline). Clinical interactions involving bupropion and coadministered CYP2D6 substrates desipramine (Shad and Preskorn 1997;Jefferson et al., 2005), dextromethorphan (Güzey et al., 2002;Kotlyar et al., 2005), and venlafaxine (Kennedy et al., 2002) are well documented. However, CYP2D6 plays an insignificant role in bupropion clearance. In humans, bupropion is extensively metabolized to three active metabolites: hydroxybupropion, which is formed primarily via CYP2B6, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group (Schroeder, 1983;Golden et al., 1988;Faucette et al., 2000;Hesse et al., 2000). Presumably, the mechanism for the clinical interaction with desipramine, which is primarily eliminated via CYP2D6 (Gram, 1974;Distlerath and Guengerich, 1984;Brøsen et al., 1986), is the result of CYP2D6 inhibition by bupropion and/or its metabolite(s). However, published data show that bupropion and hydroxybupropion are weak CYP2D6 inhibitors in vitro (IC 50 ϭ 58 and 74 M, respectively) (Hesse et al., 2000). Because unbound human plasma concentrations of the active metabolites are 2.3-to 12-fold higher than bupropion levels, it is possible that the CYP2D6 inhibition observed in the clinic is the result of more potent CYP2D6 inhibition by threohydrobupropion or erythrohydrobupropion compared with bupropion and hydroxybupropion. In addition, another hypothesis...

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Section: Resultsmentioning

confidence: 71%

“…Clinical interactions involving bupropion and coadministered CYP2D6 substrates desipramine (Shad and Preskorn 1997;Jefferson et al, 2005), dextromethorphan (Güzey et al, 2002;Kotlyar et al, 2005), and venlafaxine (Kennedy et al, 2002) are well documented. However, CYP2D6 plays an insignificant role in bupropion clearance.…”

Section: Introductionmentioning

confidence: 99%

An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction

Reese

Wurm²,

Muir³

et al. 2008

Drug Metab Dispos

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“…The increase in muscle stiffness may well relate to elevation of antipsychotic drug levels through de-induction of CYP 1A2 by smoking cessation [33] or inhibition of CYP 2D6 by bupropion [34].…”

Section: Discussionmentioning

confidence: 99%

A Placebo-Controlled Trial of Bupropion Combined with Nicotine Patch for Smoking Cessation in Schizophrenia

George¹,

Vessicchio²,

Sacco³

et al. 2008

Biological Psychiatry

133

134

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“…Potential confounders included socioeconomic status (income quintiles) at cohort entry date, prior hospitalizations for bradycardia in the year prior to the index event, number of drugs prescribed in the past year [Schneeweiss et al 2001], use of other CYP2D6-inhibiting drugs in the past 90 days, and use of negative chronotropic drugs (verapamil, diltiazem, and digoxin) in the past 90 days. Although bupropion is also a CYP2D6-inhibiting antidepressant [Kotlyar et al 2005], we included it as a covariate with other CYP2D6 inhibitors rather than as an exposure antidepressant per se because its use as an adjunct for smoking cessation may have introduced bias if patients treated with bupropion were systematically different from those prescribed other antidepressants. Finally, because sertraline exhibits some CYP2D6 inhibition, particularly at high doses [Sproule et al 1997], we conducted a sensitivity analysis by removing sertraline exposure and repeating the multivariate analysis.…”

Section: Discussionmentioning

confidence: 99%

Antidepressants, metoprolol and the risk of bradycardia

Kurdyak¹,

Manno²,

Gomes³

et al. 2011

Therapeutic Advances in Psychopharmacology

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Case reports and pharmacologic theory suggest that some antidepressants can interfere with the hepatic metabolism of metoprolol by cytochrome P450 2D6 (CYP2D6), potentially increasing the risk of bradycardia. The objective of this study was to characterize the clinical consequences of this potential drug interaction at the population level. We conducted a population-based, nested case-control study of Ontario residents 66 years of age or older receiving metoprolol. Cases hospitalized for bradycardia were compared with matched controls (4:1) to explore the odds ratio for initiation of antidepressants that inhibit CYP2D6 (fluoxetine and paroxetine) and those that do not inhibit CYP2D6 (fluvoxamine, citalopram, venlafaxine, and sertraline) 30 days before hospitalization. From April 1997 to March 2009, we identified 332,254 older patients continuously receiving metoprolol, of whom 8232 (2.5%) were treated in hospital for bradycardia. The adjusted odds ratio for exposure to fluoxetine or paroxetine compared with other antidepressants 30 days prior to hospitalization for bradycardia was 0.76 (95% confidence interval 0.42-1.37). Among older patients receiving metoprolol, the initiation of antidepressants that inhibit CYP2D6 was not associated with a significant increase in the risk of bradycardia compared with antidepressants that do not inhibit CYP2D6.

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Inhibition of CYP2D6 Activity by Bupropion

Cited by 117 publications

References 24 publications

An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction

An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction

A Placebo-Controlled Trial of Bupropion Combined with Nicotine Patch for Smoking Cessation in Schizophrenia

Antidepressants, metoprolol and the risk of bradycardia

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