Backman J T, Olkkola K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki, Finland.
Clin Pharmacol Ther. 1996 Jan;59(1):7-13. doi: 10.1016/S0009-9236(96)90018-1.
Midazolam is a short-acting benzodiazepine that is metabolized by CYP3A enzymes. Rifampin is a potent enzyme inducer that may seriously interact with some substrates of CYP3A4.
The possible interaction between rifampin and midazolam was investigated in a double-blind, randomized crossover study of two phases. Rifampin (600 mg once daily) or placebo was administered to 10 healthy subjects for 5 days. On the sixth day, the subjects were given 15 mg oral midazolam. Plasma samples were collected for determination of midazolam, and pharmacodynamic effects were measured for 10 hours.
Rifampin pretreatment decreased the area under the plasma midazolam concentration-time curve by 96% (i.e., from 10.2 +/- 0.8 to 0.42 +/- 0.05 micrograms.min/ml [mean +/- SEM; p < 0.001]) and the maximum concentration by 94% (i.e., from 55 +/- 4 to 3.5 +/- 0.7 ng/ml [p < 0.001]). The elimination half-life of midazolam was decreased from 3.1 +/- 0.2 to 1.3 +/- 0.2 hours by rifampin (p < 0.001). During the rifampin phase, the pharmacodynamic effects of midazolam were markedly smaller than the effects during the placebo phase in all the tests (e.g., the Digit Symbol Substitution Test; p < 0.001).
The observed substantial decrease in plasma concentrations and effects of midazolam most likely results from induction of CYP3A4 by rifampin in both the gut wall and the liver. Orally administered midazolam is ineffective during rifampin treatment.
咪达唑仑是一种短效苯二氮䓬类药物，由细胞色素P450 3A（CYP3A）酶代谢。利福平是一种强效酶诱导剂，可能与CYP3A4的某些底物发生严重相互作用。
在一项两阶段双盲、随机交叉研究中，对利福平和咪达唑仑之间可能的相互作用进行了研究。10名健康受试者接受利福平（每日一次，600毫克）或安慰剂治疗5天。在第6天，受试者口服15毫克咪达唑仑。采集血浆样本以测定咪达唑仑，并测量10小时的药效学效应。
利福平预处理使血浆咪达唑仑浓度-时间曲线下面积降低了96%（即从10.2±0.8降至0.42±0.05微克·分钟/毫升[平均值±标准误；p<0.001]），最大浓度降低了94%（即从55±4降至3.5±0.7纳克/毫升[p<0.001]）。利福平使咪达唑仑的消除半衰期从3.1±0.2小时降至1.3±0.2小时（p<0.001）。在利福平阶段，在所有测试中，咪达唑仑的药效学效应均明显小于安慰剂阶段（例如数字符号替换测试；p<0.001）。
观察到的咪达唑仑血浆浓度和效应的大幅降低很可能是由于利福平在肠壁和肝脏中诱导CYP3A4所致。在利福平治疗期间，口服咪达唑仑无效。
