TY - JOUR T1 - Gene Variants in CYP2C19 are Associated with Altered In Vivo Bupropion Pharmacokinetics but not Bupropion Assisted Smoking Cessation Outcomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.114.060285 SP - dmd.114.060285 AU - Andy Z.X. Zhu AU - Qian Zhou AU - Lisa Sanderson Cox AU - Jasjit S. Ahluwalia AU - Neal L. Benowitz AU - Rachel F. Tyndale Y1 - 2014/09/03 UR - http://dmd.aspetjournals.org/content/early/2014/09/03/dmd.114.060285.abstract N2 - 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 AUC, but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670h.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. ER -