RT Journal Article
SR Electronic
T1 THIENOPYRIDINES, BUT NOT ELINOGREL, RESULT IN OFF-TARGET EFFECTS AT THE VESSEL WALL THAT CONTRIBUTE TO BLEEDING
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.110.178574
DO 10.1124/jpet.110.178574
A1 Patrick Andre
A1 Francis DeGuzman
A1 Helena Haberstock-Debic
A1 Scott Mills
A1 Yvonne Pak
A1 Mayuko Inagaki
A1 Anjali Pandey
A1 Stanley Hollenbach
A1 David Phillips
A1 Pamela Conley
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/03/29/jpet.110.178574.abstract
AB 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.