Ma J D, Lawendy N M, Fullerton T, Snyder P J, Nafziger A N, Bertino J S
Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, NY, USA.
Int J Clin Pharmacol Ther. 2009 Feb;47(2):111-9. doi: 10.5414/cpp47111.
Phenotyping intestinal and hepatic cytochrome P450 (CYP) 3A activity with oral midazolam can be limited by midazolam-induced central nervous system (CNS) side effects. Determining methods to minimize CNS side effects optimizes use of midazolam as a CYP3A probe.
The objective of this study was to determine the effect of intravenous (i.v.) flumazenil on midazolam apparent oral clearance (a surrogate marker of CYP3A activity). Midazolam pharmacodynamics were also evaluated.
This was a randomized, double-blind, placebo-controlled, single-dose, two-way crossover study. 16 healthy volunteers (8 women) were concomitantly administered i.v. flumazenil 0.005 mg/kg or i.v. placebo and oral midazolam 0.075 mg/kg. Blood samples were obtained to determine midazolam and flumazenil plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMR) and 90% confidence intervals (90% CI). Baseline and post dose digit symbol substitution tests (DSST), Groton maze learning tests (GMLT), and Stanford sleepiness scales (SSS) were conducted.
Apparent oral clearance was 2,030 +/- 651 and 1,939 +/- 658 ml/min for the midazolam plus flumazenil and midazolam plus placebo groups. Equivalence in midazolam apparent oral clearance was observed (%GMR flumazenil/placebo, 90% CI 104.8, 94 - 116.6%). Flumazenil partially attenuated oral midazolam pharmacodynamics. Exploratory post hoc analyses revealed that midazolam exposure was 1.9-fold higher in men compared to women.
i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.
口服咪达唑仑对肠道和肝脏细胞色素P450（CYP）3A活性进行表型分析可能会受到咪达唑仑诱导的中枢神经系统（CNS）副作用的限制。确定将CNS副作用降至最低的方法可优化咪达唑仑作为CYP3A探针的使用。
本研究的目的是确定静脉注射（i.v.）氟马西尼对咪达唑仑表观口服清除率（CYP3A活性的替代标志物）的影响。还评估了咪达唑仑的药效学。
这是一项随机、双盲、安慰剂对照、单剂量、双向交叉研究。16名健康志愿者（8名女性）同时接受静脉注射0.005mg/kg氟马西尼或静脉注射安慰剂以及口服0.075mg/kg咪达唑仑。采集血样以测定咪达唑仑和氟马西尼的血浆浓度。通过确定几何平均比值（GMR）和90%置信区间（90%CI）来评估生物等效性。进行基线和给药后数字符号替换测试（DSST）、格罗顿迷宫学习测试（GMLT）和斯坦福嗜睡量表（SSS）。
咪达唑仑加氟马西尼组和咪达唑仑加安慰剂组的表观口服清除率分别为2030±651和1939±658ml/min。观察到咪达唑仑表观口服清除率具有等效性（氟马西尼/安慰剂的%GMR，90%CI为104.8，94 - 116.6%）。氟马西尼部分减弱了口服咪达唑仑的药效学。探索性事后分析显示，男性的咪达唑仑暴露量比女性高1.9倍。
静脉注射氟马西尼可与口服咪达唑仑联合用于CYP3A表型分析。
