Pharmacogenetic influence on bupropion bioactivation and clinical outcomes in major depressive disorder

J Pharmacol Exp Ther. 2026 Jan 30;393(3):103818. doi: 10.1016/j.jpet.2026.103818. Online ahead of print.

ABSTRACT

This investigation addressed influences of CYP2B6 and CYP2C19 genetic polymorphisms on steady-state bupropion disposition, antidepressant outcomes and side effects, and evaluated influences of pharmacokinetic variability on pharmacogenetic results. This was a preplanned secondary analysis of a prospective, 24-week, randomized, double-blind, crossover trial which compared pharmacokinetics and antidepressant effects across brand and 3 generic bupropion XL 300 mg drug products in 70 participants with major depressive disorder in remission, who were genotyped for CYP2B6 and CYP2C19 polymorphisms. We measured steady-state enantiomeric plasma and urine bupropion and primary (hydroxybupropion, a bioactivation pathway), reduced, and secondary metabolites, clinical depression (Montgomery-Asberg depression rating scale), side effects, and influence of CYP2B6 and CYP2C19 polymorphisms on bupropion disposition and drug effects across all 4 drug products (pooled analysis). Results showed that CYP2B6 polymorphisms (CYP2B6∗6 allele and the 516G>T variant alone) had a significant influence on bupropion disposition, including apparent oral clearance and enantiomers hydroxylation. Since bioactivation via bupropion hydroxylation has therapeutic importance, CYP2B6 polymorphisms could be clinically relevant. However, there were no significant differences between CYP2B6∗6 or 516G>T gene groups in either depression or side effect scores, at baseline on patients’ own bupropion, or during the crossover phase of 4 bupropion products. CYP2C19 polymorphisms had a small and clinically unimportant influence on bupropion minor metabolites and secondary metabolism, and no effect on depression or side effect scores. Results show that CYP2B6 polymorphisms significantly influenced bupropion enantiomers steady-state disposition, but not long-term antidepressant or side effects. These findings may have relevance for clinical pharmacogenetic testing in depression. SIGNIFICANCE STATEMENT: This pharmacogenetic study in major depressive disorder evaluated both pharmacokinetics and clinical effects. CYP2B6 polymorphisms (CYP2B6∗6 allele, 516G>T variant) had significant influence on steady-state bupropion enantiomers apparent oral clearance and hydroxylation, but there was no association between CYP2B6∗6 or 516G>T gene groups and either depression or drug side effects. CYP2C19 polymorphisms had a small and clinically unimportant influence on bupropion minor metabolites and secondary metabolism and no effect on depression or side effect scores. These results may have implications for genetic testing in bupropion pharmacotherapy of major depressive disorder.

PMID:41759239 | DOI:10.1016/j.jpet.2026.103818