title: Pharmacokinetics of vicagrel, a promising analog of clopidogrel, in rats and beagle dogs.
abstract: The objective of this investigation was to compare the efficiency of conversion to the active metabolite (AM) from clopidogrel and vicagrel, a novel antiplatelet agent, and support the drug design rationale in the view of the pharmacokinetics. Following intravenous administration to rats, vicagrel was rapidly converted to its thiolactone intermediate (2-oxo-clopidogrel), then to the AM. The transformation efficiency of vicagrel to 2-oxo-clopidogrel was 94%, but only 13% of clopidogrel was converted to 2-oxo-clopidogrel. Compared with the clopidogrel following oral administration to rats and beagle dogs at equal molar doses, vicagrel increased the exposure to 2-oxo-clopidogrel approximately sixfold (58.6 ± 10.2 vs. 10.2 ± 6.6 µg h/L in rats, 97.1 ± 51.9 vs. 16.1 ± 3.3 µg h/L in dogs) and the exposure to the AM approximately fourfold to sixfold (59.0 ± 18.8 vs. 14.4 ± 9.6 µg h/L in rats, 635.1 ± 114.5 vs. 99.0 ± 10.3 µg h/L in dogs). The rapid and extensive conversion of vicagrel to the intermediate 2-oxo-clopidogrel by esterase instead of cytochrome P450s (CYPs) makes the novel prodrug vicagrel a promising agent to prevent platelet aggregation and overcome clopidogrel resistance and high interindividual variability due to CYP2C19 polymorphism.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Fengjie
authors.initials: F
authors.lastname: Tian
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000077144:Clopidogrel; D004285:Dogs; D005260:Female; D008297:Male; D010648:Phenylacetates / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D010648:Phenylacetates; D013876:Thiophenes; C574646:methyl 2-(2-acetoxy-6,7-dihydrothieno(3,2-c)pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate; D000077144:Clopidogrel; D013988:Ticlopidine