Abstract
Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y12 and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl3-induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y12(−/−) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y12. Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y12(−/−) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y12 activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the 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, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.
Footnotes
All coauthors are employees and shareholders of Portola Pharmaceuticals.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.178574.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- TRITON-TIMI 38
- Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction
- WT
- wild-type
- PRP
- platelet-rich plasma
- TRAP
- thrombin receptor activating peptide
- aPTT
- activated partial thromboplastin time
- PT
- prothrombin time
- α,β-metATP
- α,β-methyleneadenosine 5′-triphosphate.
- Received December 22, 2010.
- Accepted March 29, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|