Klockowski P M, Levy G
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst.
J Pharmacol Exp Ther. 1988 Mar;244(3):912-8.
The purpose of this investigation was to determine the relative contribution of diazepam and its active metabolites (desmethyldiazepam, oxazepam and temazepam) to the hypnotic activity of this benzodiazepine drug and to assess the role of rate of drug administration as a determinant of the relative concentrations of diazepam and its active metabolites in serum and in the central nervous system at the onset of a predefined pharmacologic endpoint. Rats were given i.v. infusions of diazepam to onset of loss of righting reflex. Samples of cerebrospinal fluid (CSF), blood (for serum) and brain were obtained at that time and were analyzed for diazepam and its active metabolites. Based on the results of six experiments on groups of 6 to 14 rats performed at the same time of day over 11 months, the pharmacologic response of the animals was found to be relatively consistent, with little variation between rats and between experiments in body weight-normalized effective dose and in diazepam serum and CSF concentrations. All three active metabolites of diazepam were found in serum, CSF and brain; they were relatively more prominent in CSF than in serum. Variation of the diazepam infusion rate (four rates between 0.10 and 0.34 mg/min per approximately 200-g rat) was associated with changes in average onset time (50 to 10 min) and dose (26 to 17 mg/kg) required to produce the pharmacologic effect. The drug and metabolite concentrations in CSF determined in these experiments, together with corresponding concentrations obtained by infusion of each active metabolite individually, yielded estimates of their relative hypnotic potency that were unaffected by differences in serum protein binding and tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
本研究的目的是确定地西泮及其活性代谢产物（去甲基地西泮、奥沙西泮和替马西泮）对这种苯二氮䓬类药物催眠活性的相对贡献，并评估给药速率作为在预定义药理学终点出现时血清和中枢神经系统中地西泮及其活性代谢产物相对浓度决定因素的作用。给大鼠静脉输注地西泮直至翻正反射消失。此时采集脑脊液（CSF）、血液（用于获取血清）和脑样本，并分析其中地西泮及其活性代谢产物。基于在11个月内每天同一时间对6至14只大鼠分组进行的6次实验结果，发现动物的药理学反应相对一致，在体重标准化有效剂量以及地西泮血清和脑脊液浓度方面，大鼠之间和实验之间几乎没有差异。地西泮的所有三种活性代谢产物均在血清、脑脊液和脑中被发现；它们在脑脊液中相对比在血清中更显著。地西泮输注速率的变化（每只约200 g大鼠0.10至0.34 mg/min之间的四个速率）与产生药理学效应所需的平均起效时间（50至10分钟）和剂量（26至17 mg/kg）的变化相关。这些实验中测定的脑脊液中药物和代谢产物浓度，以及通过单独输注每种活性代谢产物获得的相应浓度，得出了它们相对催眠效力的估计值，这些估计值不受血清蛋白结合和组织分布差异的影响。（摘要截断于250字）
