Caplain H, Donat F, Gaud C, Necciari J
Institut Aster, Hôpital Cognacq-Jay, Paris, France.
Semin Thromb Hemost. 1999;25 Suppl 2:25-8.
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.
氯吡格雷被广泛代谢，这在大多数临床试验的血浆样本中未检测到未改变的氯吡格雷量得到证明。主要的循环化合物是无活性的羧酸衍生物SR26334，口服给药后氯吡格雷的吸收和消除信息来自该代谢物的药代动力学。在一项随机、剂量比例研究中，对12名受试者口服50、75、100和150 mg单剂量氯吡格雷后SR26334的单剂量药代动力学进行了研究。SR26334的多剂量药代动力学主要来自一项对18名受试者进行的研究，这些受试者每天服用75 mg氯吡格雷，持续14天。一组35名受试者进行的长期研究结果提供了关于多剂量药代动力学的进一步数据，这些受试者每天服用75 mg氯吡格雷，持续12周。所有受试者均为健康男性志愿者，在所有情况下，氯吡格雷均在隔夜禁食后的早晨服用。单剂量50、75、100和150 mg氯吡格雷后SR26334的平均Cmax值（±标准差）分别为1.6±0.30 mg/L、2.9±0.68 mg/L、3.1±0.94 mg/L和4.9±1.22 mg/L。对剂量标准化的Cmax进行的方差分析显示无统计学显著的剂量效应，表明在该氯吡格雷剂量范围内Cmax呈剂量比例增加。SR26334的尿排泄量较低，为给药剂量 的2.2%至2.4%，并且在所有四个剂量下Cl（r - 2 - 24）基本保持恒定。各剂量之间的中位T(max)（0.8 - 1.0小时）和平均血浆t1/2（7.2 - 7.6小时）值无显著差异。重复服用75 mg氯吡格雷后，稳态下SR26334的平均（±标准差）C(trough)值（给药前的值）范围为从0.8±0.04 mg/L至0.11±0.07 mg/L。这些值与在12周氯吡格雷给药期间观察到的值相似，表明稳态值具有可重复性，并且在数月的治疗过程中氯吡格雷向其羧酸代谢物的酯酶生物转化保持恒定。
