Guentert T W
Clin Pharmacokinet. 1984 May-Jun;9(3):203-10. doi: 10.2165/00003088-198409030-00002.
Several studies investigating changes with time in pharmacokinetic parameters of several benzodiazepines are reviewed. At least 3 possibilities (enzyme induction, enzyme inhibition by metabolic products, and unchanged kinetics following long term therapy or high doses) have been postulated in the disposition processes of diazepam. It seems likely that the contradictory results which have been reported can be explained by differences in 1 or several experimental factors influencing the outcome of a study (patient compliance, multiple drug therapy or statistical design). With the 3-hydroxybenzodiazepine lorazepam and the nitro-benzodiazepine nitrazepam, no changes in metabolic activity were observed. Studies with clonazepam in monkeys have confirmed previous observations that reduced metabolic activity during periods of physical inactivity gives rise to circadian fluctuations in steady-state concentrations of the drug. Furthermore, systemic and intrinsic clearances of midazolam were found to be higher following an intravenous dose in the late afternoon than after a morning dose. The protein binding of diazepam is also subject to diurnal variations, and concomitant changes in apparent volume of distribution and clearance have been observed. From the existing data it seems likely that the rate of absorption of several benzodiazepines (including diazepam, clobazam and clorazepate) varies periodically with a 24-hour cycle, pointing to diurnal effects on drug absorption processes.
本文综述了多项关于几种苯二氮䓬类药物药代动力学参数随时间变化的研究。在地西泮的处置过程中，至少有3种可能性被提出（酶诱导、代谢产物对酶的抑制以及长期治疗或高剂量后动力学不变）。似乎已报道的相互矛盾的结果可以通过影响研究结果的1个或多个实验因素（患者依从性、多种药物治疗或统计设计）的差异来解释。对于3-羟基苯二氮䓬类药物劳拉西泮和硝基苯二氮䓬类药物硝西泮，未观察到代谢活性的变化。对猴子进行的氯硝西泮研究证实了先前的观察结果，即在身体不活动期间代谢活性降低会导致药物稳态浓度出现昼夜波动。此外，发现下午晚些时候静脉注射咪达唑仑后的全身清除率和内在清除率高于早晨给药后。地西泮的蛋白结合也存在昼夜变化，并且观察到分布容积和清除率的相应变化。从现有数据来看，几种苯二氮䓬类药物（包括地西泮、氯巴占和氯氮䓬）的吸收速率似乎以24小时周期周期性变化，这表明昼夜对药物吸收过程有影响。
