Pentikis Helen S, Connolly Margaret, Trapnell Carol B, Forbes William P, Bettenhausen Doug K
ICON Development Solutions, Ellicott City, Maryland, USA.
Pharmacotherapy. 2007 Oct;27(10):1361-9. doi: 10.1592/phco.27.10.1361.
To evaluate the potential of rifaximin, an oral nonabsorbed (< 0.4%) structural analog of rifampin, to induce human hepatic and/or intestinal cytochrome P450 (CYP) 3A enzymes, with use of a known CYP3A probe, midazolam.
Prospective, randomized, open-label, two-period, crossover study.
Clinical research center.
Twenty-seven healthy adult volunteers.
During the first treatment period, subjects received a single dose of either intravenous midazolam 2 mg over 30 minutes or oral midazolam 6 mg on day 0. From days 3-10, they received rifaximin 200 mg every 8 hours. On days 6 (after the 9th dose of rifaximin) and 10 (after the 21st dose of rifaximin), subjects received a concomitant single dose of intravenous or oral midazolam. After a 15-day washout period, subjects were crossed over to the other formulation of midazolam, and the treatment schedule was repeated, with the second treatment period starting on day 26 and single-dose administration of midazolam on days 26, 32, and 36. Serial plasma samples were collected for pharmacokinetic analyses.
The pharmacokinetic parameters of single-dose intravenous or oral midazolam were determined alone and after coadministration of rifaximin for 3 and 7 days. Rifaximin coadministration did not alter the measured pharmacokinetic parameters for midazolam or its major metabolite, 1'-hydroxymidazolam. The 90% confidence intervals for the maximum concentration and area under the concentration-time curve from time zero extrapolated to infinity (bioavailability) were all within 80-125% for intravenous and oral midazolam. Therefore, no drug interaction was observed between rifaximin and midazolam. Coadministration of midazolam and rifaximin was well tolerated.
Overall, 3-7 days of rifaximin 200 mg 3 times/day did not alter single-dose midazolam pharmacokinetics. Rifaximin also does not appear to induce intestinal or hepatic CYP3A activity.
使用已知的CYP3A探针咪达唑仑，评估利福昔明（一种口服不吸收的（<0.4%）利福平结构类似物）诱导人肝和/或肠道细胞色素P450（CYP）3A酶的潜力。
前瞻性、随机、开放标签、两期交叉研究。
临床研究中心。
27名健康成年志愿者。
在第一个治疗期，受试者于第0天接受单次静脉注射咪达唑仑2mg，持续30分钟，或口服咪达唑仑6mg。从第3 - 10天，他们每8小时接受一次利福昔明200mg。在第6天（第9次服用利福昔明后）和第10天（第21次服用利福昔明后），受试者接受单次静脉或口服咪达唑仑。经过15天的洗脱期后，受试者交叉接受另一种咪达唑仑制剂，重复治疗方案，第二个治疗期从第26天开始，在第26、32和36天单次给予咪达唑仑。采集系列血浆样本进行药代动力学分析。
分别测定单次静脉或口服咪达唑仑的药代动力学参数，以及利福昔明联合给药3天和7天后的参数。联合使用利福昔明未改变所测咪达唑仑及其主要代谢产物1'-羟基咪达唑仑的药代动力学参数。静脉和口服咪达唑仑的最大浓度以及从时间零外推至无穷大的浓度-时间曲线下面积（生物利用度）的90%置信区间均在80 - 125%范围内。因此，未观察到利福昔明与咪达唑仑之间存在药物相互作用。咪达唑仑和利福昔明联合给药耐受性良好。
总体而言，每天3次服用200mg利福昔明，持续3 - 7天，未改变单次服用咪达唑仑的药代动力学。利福昔明似乎也不会诱导肠道或肝脏CYP3A活性。
