Disposition and metabolic fate of prasugrel in mice, rats, and dogs

Abstract

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.

Key Words::

• Prasugrel metabolism and disposition
• thienopyridine
• ester hydrolysis
• thiol metabolites
• S-methylation
• cysteine conjugation
• species comparison

Acknowledgements

The authors acknowledge the excellent assistance provided by Julie Sherman of Eli Lilly and Company for the figure creation and administrative assistance in the preparation of this manuscript. A portion of this work was presented at the 7th International ISSX Meeting, Vancouver, BC, Canada, 2004, and was published in abstract form in Drug Metabolism Reviews, volume 36 (Suppl. 1), p. 242.