Clopidogrel and drug metabolism: Absence of effect on hepatic enzymes in healthy volunteers

The influence of clopidogrel 75 mg, given once daily for 10 days on hepatic P-450 mixed function oxidases, was examined by assessing its effect on the disposition of antipyrine, on urinary 6-beta-hydroxycortisol (6 beta-OHC) and on the plasma activity of gamma-glutamyl transpeptidase. This double-bl ind, randomized, placebo-controlled study was conducted in two parallel gro ups of 10 healthy young volunteers. Subjects were required to fast for 12 h ours before and for 4 hours after dosing, Antipyrine 10 mg/kg was administe red in the morning, two days before treatment (day -2) and 24 hours after t he last dose of clopidogrel or placebo. Plasma levels of antipyrine, and ur inary excretion of antipyrine, 3-hydroxymethyl-antipyrine and nor-antipyrin e were measured over 36 hours post-drug for pharmacokinetic determinations. Bleeding time and platelet aggregation induced by 5 mu M of ADP were measu red before treatment (baseline) and at regular intervals after dosing durin g treatment. Clopidogrel treatment had a marked effect on platelet aggregat ion and bleeding time. No significant change in the disposition of antipyri ne was observed after the ingestion of clopidogrel over 10 days: mean AUC r atio (+/-SEM) for plasma antipyrine was 1.021 +/- 0.023 for the clopidogrel group versus 1.001 +/- 0.019 for the placebo group; mean day 10/day -2 t(1 /2) ratios were 1.019 +/- 0.018 and 1.027 +/- 0.023, respectively. Urinary excretions of antipyrine and metabolites were unchanged by clopidogrel comp ared to placebo. The changes in plasma cortisol concentrations, 6 beta-OHC excretion and serum gamma-glutamyl transpeptidase activities observed at th e end of treatment were fully comparable between the two treatment groups. Thus, the different tests showed no evidence of hepatic enzyme induction by clopidogrel in a pharmacologically effective dose regimen.