Rogers Janyce F, Morrison Ashley L, Nafziger Anne N, Jones Connie L, Rocci Mario L, Bertino Joseph S
Clinical Pharmacology Research Center and Department of Medicine, Bassett Healthcare, Cooperstown, NY 13326-1394, USA.
Clin Pharmacol Ther. 2002 Dec;72(6):711-7. doi: 10.1067/mcp.2002.128866.
Intravenous midazolam is used as an in vivo biomarker of hepatic cytochrome P450 (CYP) 3A activity. Midazolam is a central nervous system depressant and can produce cognitive impairment. The purpose of this study was 2-fold: (1) to determine whether administration of intravenous flumazenil given before intravenous midazolam minimizes cognitive impairment and (2) to determine whether flumazenil pretreatment has an effect on midazolam pharmacokinetics during hepatic CYP3A phenotyping.
Eleven healthy subjects (8 men) received intravenous flumazenil (0.005 mg/kg) or placebo followed 7 minutes later by intravenous midazolam (0.025 mg/kg) in a randomized, double-blind crossover study. Plasma midazolam concentrations were obtained before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing and were assayed by liquid chromatography-tandem mass spectrometry. Midazolam pharmacokinetics were determined by noncompartmental methods. The two 1-sided tests procedure was used to compare area under the curve (AUC) between study phases. Data were log-transformed before analysis, and bioequivalence criteria were applied. Digit symbol substitution tests, performed before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing, were used to measure cognition. General linear modeling was used to compare scores between study phases.
Midazolam AUC extrapolated to infinity [AUC(0-infinity)] between phases was bioequivalent. The AUC ratio (flumazenil plus midazolam/midazolam) was 0.99, with a 90% confidence interval of 0.98 to 1.00. Statistically significant differences(P <or=.05) in digit symbol substitution test scores between phases were determined relative to time and a phase-by-time interaction.
Flumazenil minimizes midazolam-induced cognitive impairment without influencing midazolam pharmacokinetics. However, the risk of side effects (ie, panic attack) caused by flumazenil should be thoroughly considered before implementation of this drug combination during phenotyping in healthy subjects.
静脉注射咪达唑仑用作肝细胞色素P450（CYP）3A活性的体内生物标志物。咪达唑仑是一种中枢神经系统抑制剂，可导致认知功能损害。本研究目的有两个：（1）确定在静脉注射咪达唑仑前给予静脉注射氟马西尼是否可将认知功能损害降至最低；（2）确定氟马西尼预处理在肝脏CYP3A表型分析期间对咪达唑仑药代动力学是否有影响。
在一项随机、双盲交叉研究中，11名健康受试者（8名男性）接受静脉注射氟马西尼（0.005mg/kg）或安慰剂，7分钟后再接受静脉注射咪达唑仑（0.025mg/kg）。给药前以及给药后5、30、60、120、240、300和360分钟采集血浆咪达唑仑浓度，采用液相色谱-串联质谱法进行测定。采用非房室方法确定咪达唑仑药代动力学。采用双向单侧检验程序比较研究阶段之间的曲线下面积（AUC）。分析前对数据进行对数转换，并应用生物等效性标准。在给药前以及给药后5、30、60、120、240、300和360分钟进行数字符号替换试验，以测量认知功能。采用一般线性模型比较研究阶段之间的得分。
各阶段之间外推至无穷大的咪达唑仑AUC [AUC(0-∞)]具有生物等效性。AUC比值（氟马西尼加咪达唑仑/咪达唑仑）为0.99，90%置信区间为0.98至1.00。相对于时间以及阶段与时间的交互作用，确定各阶段之间数字符号替换试验得分存在统计学显著差异（P≤0.05）。
氟马西尼可将咪达唑仑引起的认知功能损害降至最低，且不影响咪达唑仑药代动力学。然而，在健康受试者表型分析期间实施这种药物组合之前，应充分考虑氟马西尼引起副作用（即惊恐发作）的风险。
