Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes

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.

Pharmacokinetics of Bupropion and Its Pharmacologically Active Metabolites in Pregnancy

“…These results are consistent with the effect of CYP2C19 polymorphism on TB and EB in nonpregnant subjects (Zhu et al, 2014). However, it appears that CYP2C19 metabolizer phenotype did not influence the levels of BUP and, consequently, its AUC ss and Cl/F ss in pregnant subjects in our study.…”

“…These data suggest an increase in the reductive metabolism of BUP in pregnancy. However, CYP2C19 also contributes to the hydroxylation of BUP and its metabolites, TB and EB (Chen et al, 2010;Zhu et al, 2014). We observed that, relative to late pregnancy, the AUC ss of EB was higher in mid-pregnancy, suggesting a decreased rate of EB metabolism in mid-pregnancy, possibly due to pregnancy-induced downregulation of CYP2C19 (McGready et al, 2003).…”

“…The most common alleles of CYP2C19 are the loss-of-function variants CYP2C19*2 (681G.A, rs4244285) and *3 (636G.A; rs4986893), and the gain-of-function variant CYP2C19*17 (-806C.T; rs12248560) (Fricke-Galindo et al, 2016). The identification of these alleles in our subjects was conducted as described by Zhu et al (2014); details are provided in Supplemental Materials and Methods Section 2.…”

“…In addition, CYP2C19 contributes to hydroxylation of BUP and its metabolites, TB and EB (Zhu et al, 2014). Both CYP2B6 and CYP2C19 genes are highly polymorphic, and some of the single-nucleotide polymorphisms (SNPs) have functional consequences (http://www.cypalleles.ki.se/).…”

Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

“…2A). Notably, whereas CYP2B enzymes play a major role in bupropion hydroxylation, other P450 enzymes, including CYP2C and CYP2E1, have been found to have low activity levels toward bupropion (Faucette et al, 2000;Chen et al, 2010;Pekthong et al, 2012;Zhu et al, 2014). However, the induction and sex difference of these non-CYP2B6 activities do not account for the sex difference in bupropion hydroxylase activities seen in the CYP2B6-humanized mice ( Fig.…”