Clopidogrel is a prodrug that requires bioactivation by cytochrome P450 (P450) enzymes to a pharmacologically active metabolite for antiplatelet action. The clinical limitations of clopidogrel are in large part due to its poor pharmacokinetics resulting from inefficient bioactivation by P450s. In this study, we determined the pharmacokinetics and pharmacodynamics of a novel conjugate of clopidogrel, referred to as ClopNPT, in animal models and we evaluated its potential to overcome the limitations of clopidogrel. Results from pharmacokinetic (PK) studies showed that ClopNPT released the active metabolite with a time to maximal plasma concentration of <5 minutes in C57BL/6 mice after either oral or intravenous administration, and plasma concentrations of the active metabolite reached Cmax values of 1242 and 1100 ng/ml after a 10-mg/kg oral dose and a 5-mg/kg intravenous dose, respectively. Furthermore, ClopNPT was highly effective in preventing arterial thrombosis in rabbits and mice after vascular injuries. Formation of occlusive thrombi was prevented by ClopNPT at the 1-mg/kg dose with no significant increase in tongue bleeding time, whereas clopidogrel was ineffective at the same dose. These results suggest that ClopNPT has favorable PK/pharmacodynamic properties that can potentially overcome the attenuated PK properties of clopidogrel and thus significantly improve the efficacy of antiplatelet therapy.
- Received June 20, 2016.
- Accepted August 9, 2016.
This research was supported by the University of Michigan Center for Discovery of New Medicine; National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01 HL088419 and R01 HL068878]; National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM077430]; and National Institutes of Health National Cancer Institute [Grant P30 CA046952]. H.Z. and P.F.H. are inventors of a patent application (US 2015/0353492 A1) and receive royalties from Diapin Therapeutics LLC.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics