Greenblatt D J, Shader R I, MacLeod S M, Sellers E M
Clin Pharmacokinet. 1978 Sep-Oct;3(5):381-94. doi: 10.2165/00003088-197803050-00004.
Chlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biotransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (tl/2beta) of chlordiazepoxide following single doses, in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5%. Elimination of the parent compound is mirrored by formation of the first active metabolite. Clearance of chlordiazepoxide is reduced and tl/2beta is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals. A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.
氯氮䓬是首个可供临床使用的苯二氮䓬衍生物。氯氮䓬的代谢途径较为复杂，因为该药物会生物转化为一系列具有药理活性的产物：去甲基氯氮䓬、地莫西泮、去甲西泮和奥沙西泮。在健康个体中，单次给药后氯氮䓬的消除半衰期（t1/2β）一般为5至30小时，分布容积为0.25至0.50升/千克。肝提取率远低于5%。母体化合物的消除与首个活性代谢产物的形成呈镜像关系。在老年人、肝硬化患者以及同时接受双硫仑治疗的患者中，氯氮䓬的清除率降低，t1/2β延长。口服氯氮䓬吸收迅速且完全，但肌肉注射会引起疼痛，且吸收缓慢且不稳定。氯氮䓬多剂量治疗会导致母体化合物及其两种或更多种活性代谢产物蓄积。个体之间的蓄积速率和程度差异很大。一些研究表明氯氮䓬及其代谢产物的血浆浓度与临床效应之间存在关联，目前正在进一步研究中。
