Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans.
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-infinity by 14% and 18%, respectively, and decreased hydroxybupropion Cmax and AUC0-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.
Farid
Nagy A
NA
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. nafarid@lilly.com
Payne
Christopher D
CD
Ernest
C Steven
CS
Li
Y Grace
YG
Winters
Kenneth J
KJ
Salazar
Daniel E
DE
Small
David S
DS
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016642:Bupropion / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000737:chemistry; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D065607:Cytochrome P-450 Enzyme Inhibitors; D003692:Delayed-Action Preparations; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D011725:Pyridines; D013876:Thiophenes; C446540:thienopyridine; D016642:Bupropion; D003577:Cytochrome P-450 Enzyme System; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D000068799:Prasugrel Hydrochloride; C496215:radafaxine