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Prasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans

From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (Dr Farid, Mr Ernest, Ms Li, Dr Winters, Dr Small); Lilly Research Center, Ltd, Eli Lilly and Company, Windlesham, UK (Mr Payne); and Daiichi Sankyo Pharma Development, Daiichi Sankyo, Inc, Edison, New Jersey (Dr Salazar). A portion of this work was presented at the 14th North American ISSX Meeting, Rio Grande, Puerto Rico, 2006, and was published in an abstract form in Drug Metab Rev. 2006;38(suppl 2):121.

Prasugrel, a thienopyridine prodrug, is hydrolyzed in vivo 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- by 14% and 18%, respectively, and decreased hydroxybupropion C_max and AUC_0- by 32% and 23%. These results are consistent with patients receiving prasugrel not requiring dose adjustments when treated with drugs primarily metabolized by CYP2B6.

Key Words: Bupropion • CYP2B6 inhibition • hydroxybupropion • prasugrel • thienopyridines • drug interactions

Address for reprints: Nagy A. Farid, PhD, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285; e-mail: nafarid{at}lilly.com.

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