Thiffault J, Landriault H, Gossard D, Raymond M, Caille G, Spenard J
Department of Pharmacology, Universite de Montreal, Canada.
Biopharm Drug Dispos. 1996 Mar;17(2):107-15. doi: 10.1002/(SICI)1099-081X(199603)17:2<107::AID-BDD936>3.0.CO;2-L.
Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for Cmin (mean (SD) = 47 center dot 2 (25 center dot 8) against 39 center dot 6 (21 center dot 1) ng mL-1, p = 0 center dot 038), AUC0-24 (2008 (814) against 1754 (714) ng h mL-1, p = 0 center dot 024), and AUC0-48 (2662 (1244) against 2395 (238) ng h mL-1, p = 0 center dot 034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.
23名年轻、健康的男性志愿者采用随机交叉设计，于上午8点（AM）或晚上10点（HS）接受每日一次、剂量为240毫克的地尔硫䓬制剂，持续6天。两种给药方式之间有7天的洗脱期。每小时监测地尔硫䓬血浆浓度，持续24小时，并在最后一剂后30、36和48小时进行监测。发现上午给药和晚上给药在最低血药浓度（平均值（标准差）=47.2（25.8）对39.6（21.1）纳克/毫升，p=0.038）、药时曲线下面积AUC0-24（2008（814）对1754（714）纳克·小时/毫升，p=0.024）和AUC0-48（2662（1244）对2395（238）纳克·小时/毫升，p=0.034）方面存在差异。总体而言，两种给药方式未产生生物等效的药代动力学曲线。此外，晚上给药在心血管事件发生率较高的清晨时段，地尔硫䓬的血浆浓度显著更高。如果假设血浆浓度与心肌保护之间存在强相关性，那么对于地尔硫䓬的每日一次制剂，应推荐晚上给药。应进行临床研究以证实这一理论药代动力学优势。
