The disposition and metabolism of prasugrel, a thienopyridine prodrug and a potent inhibitor of platelet aggregation in vivo, were investigated in mice, rats, and dogs. Prasugrel was rapidly absorbed and extensively metabolized. In the mouse and dog, maximum plasma concentration of radioactivity was observed in less than 1 h after an oral [14C]prasugrel dose. Most of the administered prasugrel dose was recovered in the faeces of rats and dogs (72% and 52-73%, respectively), and in mice urine (54%). Prasugrel is hydrolysed by esterases to a thiolactone, which is subsequently metabolized to thiol-containing metabolites. The main circulating thiol-containing metabolite in the three animal species is the pharmacologically active metabolite, R-138727. The thiol-containing metabolites are further metabolized by S-methylation and conjugation with cysteine.