Clinical studies with clopidogrel or prasugrel show that while increased inhibition of P2Y12 and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We utilized multiple in vivo (FeCl3-induced arterial thrombosis in mesenteric arteries; blood loss following tail trans-section; platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, PT, aPTT) mouse models to: i) compare the TI of clopidogrel, prasugrel and elinogrel, a reversible, competitive antagonist, with that of P2Y12-/- mice. ii) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y12. Data indicated greater (elinogrel) and decreased (thienopyridines) TI when compared to P2Y12-/- mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y12 activities on platelet function or coagulation but related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y12-independent off-target effects at the vessel wall while that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.
- Received December 22, 2010.
- Revision received March 28, 2011.
- Accepted March 29, 2011.
- The American Society for Pharmacology and Experimental Therapeutics