Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans

Prasugrel, a thienopyridine prodrug, is hydrolyzed in Ova by esterases to a thiolactone followed by a single cytochrome P450 (CYP)-dependent step to an active metabolite that is a potent inhibitor of adenosine diphosphate-induced platelet aggregation. This open-label, multiple-dose, 2-period, fixed-sequence study assessed CYP2B6 inhibition by prasugrel using bupropion as a probe substrate, where its active metabolite, hydroxybupropion, is almost exclusively formed by CYP2B6. Thirty healthy subjects received a single 150-mg oral dose of sustained-release bupropion. After a 7-day washout, a 60-mg prasugrel loading dose, followed by a 10-mg daily maintenance dose for 10 days, was administered. Bupropion (150 mg) was given with prasugrel on day 7 of this phase. Prasugrel weakly inhibited CYP2B6 activity as it increased bupropion C-max and AUC(0-infinity) by 14% and 18%, respectively, and decreased hydroxybupropion C-max and AUC(0-infinity) by 32% and 23%. These results are consistent with patients receiving prasugrel not requiring dose adjustments when treated with drugs primarily metabolized by CYP2B6.