Caplain H, Thebault J J, Necciari J
Institut Aster, Hôpital Cognacq-Jay, Paris, France.
Semin Thromb Hemost. 1999;25 Suppl 2:65-8.
The potential influence of clopidogrel on the pharmacokinetics of theophylline was evaluated in 15 healthy male subjects during the pharmacokinetic steady state of theophylline, after single and multiple doses. Theophylline was administered orally as one 300-mg capsule in the morning before breakfast and one in the evening before dinner for 13 days (day 1 through day 13), and one capsule on the morning of day 14. Clopidogrel was administered orally as one 75-mg tablet in the morning before breakfast from day 5 through day 14. Plasma concentration of theophylline was determined at the following times: before the morning dose on days, 1, 6-9, and 12; before administration, then at 0.5, 1,2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after administration on days 4, 5, and 14. Tests of hemostasis (ADP-induced platelet aggregation and bleeding time) were carried out 2 hours after clopidogrel dosing on days 5, 7, 9, 11, and 14. The curves of the mean plasma concentration of theophylline over 12 hours post-morning dose on day 4 (drug alone), day 5 (after a single dose of clopidogrel), and day 14 (after 10 days of clopidogrel coadministration) were superimposable, indicating the absence of an effect of clopidogrel on the steady-state pharmacokinetics of theophylline. There were no statistically significant differences between the days of administration for the log-transformed values of theophylline C(bt) (concentration before treatment) Cmax, AUC(0-12h), and Cmin; and the 90% confidence intervals of the day 5/day 4, day 14/day 4, and day 14/day 5 ratios of the geometric means of C(bt) all fell within the (0.80; 1.25) interval. These results show that the administration of clopidogrel during steady state theophylline administration had no effect on the plasma concentration of the latter drug. The average steady-state (days 11-14) percentage of inhibition of ADP-induced platelet aggregation by clopidogrel with respect to day 1 was 46%. The geometric mean of the bleeding time prolongation factor was about 2 at steady state. The latter results indicate that the pharmacodynamics of clopidogrel were not affected by concomitant theophylline.
在15名健康男性受试者处于茶碱药代动力学稳态时，评估了氯吡格雷对茶碱药代动力学的潜在影响，给药方式为单剂量和多剂量。茶碱在早餐前的早晨口服1粒300毫克胶囊，晚餐前的晚上口服1粒，持续13天（第1天至第13天），并在第14天早晨口服1粒胶囊。氯吡格雷从第5天至第14天在早餐前的早晨口服1片75毫克片剂。在以下时间点测定茶碱的血浆浓度：第1、6 - 9和12天早晨给药前；第4、5和14天给药前，给药后0.5、1、2、3、4、5、6、7、8、10和12小时。在第5、7、9、11和14天氯吡格雷给药2小时后进行止血测试（ADP诱导的血小板聚集和出血时间）。第4天（仅用药）、第5天（单剂量氯吡格雷后）和第14天（氯吡格雷联合给药10天后）早晨给药后12小时内茶碱平均血浆浓度曲线可叠加，表明氯吡格雷对茶碱的稳态药代动力学无影响。茶碱C(bt)（治疗前浓度）、Cmax、AUC(0 - 12h)和Cmin的对数转换值在给药天数之间无统计学显著差异；第5天/第4天、第14天/第4天和第14天/第5天C(bt)几何均值比值的90%置信区间均落在(0.80; 1.25)区间内。这些结果表明，在茶碱稳态给药期间给予氯吡格雷对后一种药物的血浆浓度无影响。与第1天相比，氯吡格雷在稳态（第11 - 14天）时对ADP诱导的血小板聚集的平均抑制百分比为46%。稳态时出血时间延长因子的几何均值约为2。后一结果表明，氯吡格雷的药效学不受同时使用茶碱的影响。
