Kassai A, Toth G, Eichelbaum M, Klotz U
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, West Germany.
Clin Pharmacokinet. 1988 Nov;15(5):319-25. doi: 10.2165/00003088-198815050-00004.
The benzodiazepine midazolam is rapidly eliminated by oxidative metabolism. In young healthy volunteers elimination half-life (t1/2) is about 2.4 hours. A recent study showed a prolonged t1/2 from 8 to 22 hours in 6.5% of surgical patients, and a genetic polymorphism of midazolam's metabolism has been suggested. Therefore, we measured in 168 surgical patients the elimination of midazolam and its major hydroxylated metabolite (alpha-OH-midazolam) in blood and urine. Co-medication, disease status, smoking habits and alcohol intake were recorded; normal liver and kidney functions were assessed by routine laboratory tests. Midazolam was administered intravenously (0.1 to 0.2 mg/kg) for the induction of anaesthesia. Blood was drawn 1.5, 3, 4.5 and 6 hours after application and urine was collected for 6 hours. Plasma protein binding of midazolam was determined by equilibrium dialysis. Midazolam and alpha-OH-midazolam were measured in plasma by specific gas-liquid chromatography and in urine by high performance liquid chromatography. Data for the dose-corrected area under plasma-level curve of midazolam (AUC-midazolam/dose: 1.23 +/- 961 x 10(5) h/ml; mean +/- SD) and for the metabolic plasma ratio (AUC of alpha-OH-midazolam/AUC-midazolam: 0.52 +/- 0.28) demonstrated a log-normal distribution. Likewise, the percentage of the unbound fraction of midazolam in plasma (5.0 +/- 2.4%), urinary excretion of alpha-OH-midazolam (55.9 +/- 22.7% of dose) and the values for t1/2 (2.9 +/- 1.1 hours) did indicate a unimodal distribution. Age, comedication and smoking habits did not affect the disposition of midazolam. However, patients with regular intake of alcohol had a higher (p less than 0.05) metabolic ratio. Only in 3 patients could a prolonged t1/2 of midazolam from 7.5 to 10.2 hours be detected, but plasma levels and urinary excretion of alpha-OH-midazolam in those individuals were found to be normal. Therefore it is very unlikely that the oxidative metabolism of midazolam exhibits a genetic polymorphism.
苯二氮䓬类药物咪达唑仑通过氧化代谢迅速消除。在年轻健康志愿者中，消除半衰期（t1/2）约为2.4小时。最近一项研究表明，6.5%的外科手术患者t1/2延长至8至22小时，提示咪达唑仑代谢存在基因多态性。因此，我们对168例外科手术患者测定了血液和尿液中咪达唑仑及其主要羟基化代谢物（α-羟基咪达唑仑）的消除情况。记录了联合用药情况、疾病状态、吸烟习惯和酒精摄入量；通过常规实验室检查评估肝肾功能是否正常。静脉注射咪达唑仑（0.1至0.2mg/kg）用于诱导麻醉。用药后1.5、3、4.5和6小时采集血液，收集尿液6小时。通过平衡透析法测定咪达唑仑的血浆蛋白结合率。采用特定气液色谱法测定血浆中咪达唑仑和α-羟基咪达唑仑，采用高效液相色谱法测定尿液中二者含量。咪达唑仑血浆水平曲线下剂量校正面积的数据（AUC-咪达唑仑/剂量：1.23±961×10⁵h/ml；均值±标准差）以及代谢血浆比值（α-羟基咪达唑仑的AUC/咪达唑仑的AUC：0.52±0.28）呈对数正态分布。同样，血浆中咪达唑仑未结合部分的百分比（5.0±2.4%）、α-羟基咪达唑仑的尿排泄率（剂量的55.9±22.7%）以及t1/2值（2.9±1.1小时）均呈单峰分布。年龄、联合用药情况和吸烟习惯不影响咪达唑仑的处置。然而，经常饮酒的患者代谢比值较高（p<0.05）。仅在3例患者中检测到咪达唑仑t1/2从7.5延长至10.2小时，但这些个体的血浆水平和α-羟基咪达唑仑的尿排泄均正常。因此，咪达唑仑的氧化代谢极不可能表现出基因多态性。
