Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in , , and on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the allele and in carriers of the 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by variants. polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) , and genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in and 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.