Clopidogrel is extensively metabolized, as evidenced by the absence of detectable amounts of unchanged clopidogrel in plasma samples in most clinical trials. The major circulating compound is the inactive carboxylic acid derivative SR26334, and information on the absorption and elimination of clopidogrel after oral administration is derived from the pharmacokinetics of this metabolite. Single-dose pharmacokinetics of SR26334 were investigated in a randomized, dose-proportionality study comparing single 50, 75, 100, and 150 mg oral doses of clopidogrel administered to 12 subjects. Multiple-dose pharmacokinetics of SR26334 were primarily derived from a study carried out in 18 subjects treated with clopidogrel 75 mg once daily for 14 days. Further data on multiple-dose pharmacokinetics were provided by the results of a long-term study carried out in a group of 35 subjects who received clopidogrel 75 mg once daily for 12 weeks. All subjects were healthy male volunteers and, in all cases, clopidogrel was taken in the morning after an overnight fast. The mean Cmax values (+/-SD) for SR26334 following single doses of 50, 75, 100, and 150 mg were 1.6+/-0.30 mg/L, 2.9+/-0.68 mg/L, 3.1+/-0.94 mg/L, and 4.9+/-1.22 mg/L, respectively. The ANOVA performed on dose-normalized Cmax showed no statistically significant dose effect, demonstrating a dose-proportional increase of Cmax in this range of clopidogrel doses. The urinary excretion of SR26334 was low-2.2 to 2.4% of the dose administered-and Cl(r-2-24) remained virtually constant at all four doses. Median T(max)(0.8-1.0 hour) and mean plasma t1/2 (7.2-7.6 hours) values were not significantly different between doses. Following repeated dosing with clopidogrel 75 mg, mean (+/-SD) C(trough) values (values before dosing) for SR26334 at steady state ranged from 0.8+/-0.04 mg/L to 0.11+/-0.07 mg/L. These values are similar to those observed during the 12-week administration of clopidogrel indicating that steady-state values are reproducible and that the esterasic biotransformation of clopidogrel into its carboxylic acid metabolite remains constant over a number of months of treatment.