Pharmacodynamic and pharmacokinetic evaluation of clopidogrel and the carboxylic acid metabolite SR 26334 in healthy dogs

Abstract

Objective - To determine pharmacodynamic and pharmacokinetic properties of clopidogrel and the metabolite SR 26334 in dogs. Animals - 9 mixed-breed dogs. Procedures - 8 dogs received clopidogrel (mean ± SD 1.13 ± 0.17 mg/kg, PO, q 24 h) for 3 days; 5 of these dogs subsequently received a lower dose of clopidogrel (0.5 ± 0.18 mg/kg, PO, q 24 h) for 3 days. Later, 5 dogs received clopidogrel (1.09 ± 0.12 mg/kg, PO, q 24 h) for 5 days. Blood samples were collected for optical platelet aggregometry, citrated native and platelet mapping thrombelastography (TEG), and measurement of plasma drug concentrations. Impedance aggregometry was performed on samples from 3 dogs in each 3-day treatment group. Results - ADP-induced platelet aggregation decreased (mean ± SD 93 ± 6% and 80 ± 22% of baseline values, respectively) after 72 hours in dogs in both 3-day treatment groups; duration of effect ranged from ≥ 3 to > 7 days. Platelet mapping TEG and impedance aggregometry yielded similar results. Citrated native TEG was not different among groups. Clopidogrel was not detected in any samples; in dogs given 1.13 ± 0.17 mg/kg, maximum concentration of SR 26334 (mean ± SD, 0.206 ± 0.2 μg/mL) was detected 1 hour after administration. Conclusions and Clinical Relevance - Clopidogrel inhibited ADP-induced platelet aggregation in healthy dogs and may be a viable antiplatelet agent for use in dogs. Impact for Human Medicine - Pharmacodynamic effects of clopidogrel in dogs were similar to effects reported in humans; clopidogrel may be useful in studies involving dogs used to investigate human disease.