The Disposition of Prasugrel, a Novel Thienopyridine, in Humans

Abstract

ABSTRACT:Prasugrel, a prodrug, is a novel and potent inhibitor of platelet aggregation in vivo. The metabolism of prasugrel and the elimination and pharmacokinetics of its active metabolite, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid (R-138727), three inactive metabolites, and radioactivity were determined in five healthy male subjects after a single 15-mg (100 Ci) Clopidogrel and ticlopidine are thienopyridine prodrugs that are activated in vivo to pharmacologically active metabolites that bind irreversibly to the platelets' P2Y 12 receptor, thus inhibiting platelet aggregation. Studies with [14 C]clopidogrel showed that the major metabolic pathway in humans is hydrolysis of clopidogrel to an inactive acid analog; no further metabolites were reported (Lins et al., 1999). Prasugrel (Fig. 1) is a novel and potent thienopyridine prodrug that also inhibits platelet aggregation in vivo. The structure of the thiol-containing active metabolite of prasugrel, R-138727, was previously reported (Sugidachi et al., 2000(Sugidachi et al., , 2001. Similarly, the structure of the thiol-containing active metabolite of clopidogrel was determined by in vitro studies (Pereillo et al., 2002). The platelet-inhibitory activity of prasugrel and initial pharmacokinetic data were recently reported . In vivo, prasugrel is rapidly hydrolyzed to a pharmacologically inactive thiolactone (R-95913), followed by cytochrome P450-dependent ring opening to form the active metabolite R-138727 (Rehmel et al., 2006). The active metabolite of prasugrel possesses two chiral centers, and its four isomers were shown to possess varying degrees of activity toward inhibition of platelet aggregation (Hasegawa et al., 2005).The prasugrel metabolites measured in human plasma in initial studies (Asai et al., 2006) indicated that after formation of R-95913, two thiol-containing compounds are formed, R-138727 and M4, which are further metabolized by S-methylation to R-106583 and R-100932, or conjugation with cysteine to R-119251 and R-118443 (Fig. 1). Compounds R-95913, R-106583, and R-100932 were measured in plasma as indicators for absorption and exposure to prasugrel and its active metabolite. In this report, the physiologic disposition of prasugrel in healthy subjects following a 15-mg (100 Ci) p.o. dose of [14 C]prasugrel is presented. Materials and MethodsRadiolabeled Drug and Chemicals. Prasugrel hydrochloride was provided by Sankyo Co., Ltd. (Tokyo, Japan). Article, publication date, and citation information can be found at

Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12receptorsin vitro

“…A recent study by Schneider et al demonstrated a transient recovery in platelet function in patients with stable coronary artery disease during the transition from cangrelor to prasugrel but this effect was limited if prasugrel was administered 30min before the end of cangrelor infusion [17]. These observations from pharmacodynamic studies are consistent with the known pharmacokinetic profiles of thienopyridine AMs and cangrelor [7][8][9][10][11] and our current findings: it is only when cangrelor plasma levels fall sufficiently for cangrelor to dissociate from the P2Y 12 receptor that thienopyridine AMs are able to bind to the receptor. Consequently, in order for clopidogrel and prasugrel to achieve irreversible inhibition of the P2Y 12 receptor, cangrelor plasma levels must fall sufficiently (via hydrolysis to inactive metabolite) before thienopyridine AM levels fall to ineffective levels as a result of distribution to extravascular compartments.…”

“…Clopidogrel active metabolite has a distribution phase plasma half-life of approximately 30 minutes and prasugrel's active metabolite demonstrates a similar profile [8,9,10] with plasma levels of both falling rapidly to less than 0.1 mol/L in the first four hours during the distribution phase [11]. Due to the irreversible binding of the thienopyridine active metabolites to platelet P2Y 12 receptors, the inhibitory effects of clopidogrel and prasugrel persist long after the relatively short-lived active metabolites have been cleared from plasma, and normal platelet function is not restored for up to 7 days post dose.…”

Review of Prasugrel for the Secondary Prevention of Atherothrombosis

“…The pharmacokinetic properties of prasugrel and clopidogrel have been investigated in several studies and are summarized in Table 2. 12,[29][30][31][32][33][34][35][36][37][38][39][40][41][42] In contrast to clopidogrel, [43][44][45] genetic variants in CYP 2C19 genes have not been shown to affect the antiplatelet response to prasugrel. …”

“…55 This conclusion was derived from an analysis of pharmacy and medical claims in the Medco Solutions database for 9,862 patients who received a PPI, compared with 6,828 patients who did not receive a PPI following a percutaneous coronary intervention (PCI). The Society for Cardiovascular Angiography and Interventions issued a statement on May 6, [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]58 Prasugrel…”

Modulation of Clopidogrel Pharmacodynamic Response

“…Differences in the effect of CYP3A4 on the metabolism of these two drugs may account for these differences. 4,5 The second issue is whether atorvastatin, which binds to but has not been reported to inhibit CYP3A4, can also modulate the therapeutic effect of thienopyridine. The effect reported by Dr. Farid and colleagues is equivocal for clopidogrel and negative for prasugrel.…”