title: Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis.
abstract: 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.
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan haom@umich.edu.
authors: Haoming
authors: H
authors: Zhang
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: D Adam
authors: DA
authors: Lauver
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Hui
authors: H
authors: Wang
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Duxin
authors: D
authors: Sun
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Paul F
authors: PF
authors: Hollenberg
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Y Eugene
authors: YE
authors: Chen
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Yoichi
authors: Y
authors: Osawa
authors: Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
authors: Daniel T
authors: DT
authors: Eitzman
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000503:physiopathology; D000077144:Clopidogrel; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry; D011817:Rabbits; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D011725:Pyridines; D000077144:Clopidogrel; C023666:pyridine; D013988:Ticlopidine