科研之友
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摘要
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 mu g h/L in rats, 97.1 +/- 51.9 vs. 16.1 +/- 3.3 mu g h/L in dogs) and the exposure to the AM approximately fourfold to sixfold (59.0 +/- 18.8 vs. 14.4 +/- 9.6 mu g h/L in rats, 635.1 +/- 114.5 vs. 99.0 +/- 10.3 mu g 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.
