The disposition of prasugrel, a novel thienopyridine, in humans

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 microCi) p.o. dose of [(14)C]prasugrel. Prasugrel was rapidly absorbed, and maximum plasma concentrations of radioactivity and R-138727 were achieved in 30 min, indicating rapid formation of R-138727. Prasugrel was extensively metabolized in humans, first by hydrolysis to a thiolactone, followed by ring opening to form R-138727, which was further metabolized by S-methylation and conjugation with cysteine. Total radioactivity was higher in plasma than in blood, suggesting limited penetration of prasugrel metabolites into red blood cells. Approximately 70% of the dose was excreted in the urine and 25% in the feces.