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DRUG INTERACTIONS |
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 Cmax and AUC0-
by 14% and 18%, respectively, and decreased hydroxybupropion Cmax and AUC0- 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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