Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state

Abstract

Background: Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6.

Objectives: To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants.

Methods: In a genotype-guided study of 42 healthy individuals, we measured the plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion, and erythrohydrobupropion after 7 days of sustained-release bupropion dosing.

Results: CYP2B6*6 and *18 gene variants were associated with ~33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex.

Conclusion: As HB is active and its steady-state concentrations are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Because of the large individual variation within the genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary.

Figure 1

Panel A: Plasma concentrations of bupropion (BUP) and its metabolites hydroxybupropion (HB), threohydrobupropion (TB) and erythrohydrobupropion (EB) over 24 hours. Mean ± SD Panel B: Area under the 24 hour plasma concentration-time curve for bupropion and metabolites.

Figure 2

Area under the 24 hour hydroxybupropion (HB) concentration-time curve in individuals with different CYP2B6 genotypes, shown by sex and race.