Abstract
Bupropion is used clinically to treat depression and to promote smoking cessation. It is metabolized by CYP2B6 to its active metabolite hydroxybupropion, yet alterations in CYP2B6 activity have little impact on bupropion plasma levels. Furthermore, less than 10% of a bupropion dose is excreted as urinary bupropion and its characterized metabolites hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, suggesting that alternative metabolic pathways may exist. In vitro data suggested CYP2C19 could metabolize bupropion. The current study investigated the impact of functional CYP2C19 genetic variants on bupropion pharmacokinetics and treatment outcomes. In 42 healthy volunteers, CYP2C19*2 (a reduced activity allele) was associated with higher bupropion area under the plasma concentration–time curve (AUC), but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670 hours⋅ng/ml in individuals with and without CYP2C19*2, respectively (P = 0.017). CYP2C19*2 was also associated with higher threohydrobupropion and erythrohydrobupropion AUC (P < 0.005). Adjusting for CYP2B6 genotype did not alter these associations, and CYP2C19 variants did not alter the utility of the hydroxybupropion/bupropion ratio as a measure of CYP2B6 activity. Finally, in a clinical trial of 540 smokers, CYP2C19 genotype was not associated with smoking cessation outcomes, supporting the hypothesis that bupropion response is mediated by hydroxybupropion, which is not altered by CYP2C19. In conclusion, our study reports the first in vivo evidence that reduced CYP2C19 activity significantly increases the steady-state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion. These pharmacokinetic changes were not associated with differences in bupropion’s ability to promote smoking cessation in smokers, but may influence the side effects and toxicity associated with bupropion.
Footnotes
- Received July 25, 2014.
- Accepted September 3, 2014.
This work was supported by the National Institutes of Health [Grants DA020830, CA78603, CA091912, DA12393], and National Institutes of Health grants through University of California, San Francisco Clinical and Translational Science Institute Grant Number UL1 RR024131, Canadian Institutes of Health Research [Grant MOP86471], the Endowed Chair in Addiction for the Department of Psychiatry University of Toronto, grants from the Centre for Addiction and Mental Health (CAMH) and the CAMH Foundation, grants from the Canada Foundation for Innovation [Grants 20289 and 16014], and a grant from the Ontario Ministry of Research and Innovation.
N.L.B. serves as a consultant to several pharmaceutical companies that market smoking cessation medications, and has been a paid expert witness in litigation against tobacco companies. R.F.T. has participated in one-day advisory meetings for Novartis and McNeil.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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