Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation.

Objective: Our objective was to study the effect of the antiplatelet agents clopidogrel and ticlopidine on bupropion (INN, amfebutamone) hydroxylation, a probe reaction for cytochrome P450 (CYP) 2B6 activity.

Methods: Twelve healthy male volunteers took a single 150-mg oral dose of bupropion either alone or after pretreatment with 75 mg clopidogrel once daily or 250 mg ticlopidine twice daily for 4 days. On day 4, a single 150-mg oral dose of bupropion was administered. Plasma concentrations of bupropion and its CYP2B6-catalyzed metabolite, hydroxybupropion, were measured for up to 72 hours.

Results: The mean area under the plasma concentration-time curve (AUC) of hydroxybupropion calculated from time 0 to infinity was reduced by 52% ( P = .001; 95% confidence interval [CI], 39% to 66%) by clopidogrel and by 84% ( P < .0001; 95% CI, 73% to 94%) by ticlopidine. Clopidogrel reduced the AUC ratio of hydroxybupropion over bupropion by 68% ( P = .002; 95% CI, 58% to 77%) and ticlopidine by 90% ( P = .001; 95% CI, 85% to 96%). The AUC of bupropion was increased by 60% ( P = .02; 95% CI, 21% to 98%) and by 85% ( P < .0001; 95% CI, 48% to 85%) with clopidogrel and ticlopidine, respectively.

Conclusions: Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalyzed bupropion hydroxylation. Patients receiving either clopidogrel or ticlopidine are likely to require dose adjustments when treated with drugs primarily metabolized by CYP2B6.