Wala E P, Sloan J W, Martin W R, Pruitt T
Department of Anesthesiology, University of Kentucky, Lexington 40536.
Pharmacol Biochem Behav. 1991 Mar;38(3):561-7. doi: 10.1016/0091-3057(91)90014-s.
The pharmacokinetic profiles of halazepam (HL) and its metabolites, desmethyldiazepam (DMDZ), oxazepam (OX), 3-hydroxyhalazepam (OH-HL), and conjugates of oxazepam (OX-CONJ) and 3-hydroxyhalazepam (OH-HL-CONJ) were studied in 4 naive dogs following single intravenous (2 mg/kg) and oral (112.5 mg/kg) administrations of HL and in 5 dependent dogs chronically dosed with HL (450 mg/kg/day q.i.d.). HL is rapidly metabolized to DMDZ as the principal metabolite but appreciable levels of HL, OX and OH-HL were measured in plasma and the brain tissue. High levels of conjugated metabolites were measured in plasma. The steady-state plasma concentrations of HL and its unconjugated metabolites can be predicted from the single dose study. Halazepam does not serve as a simple prodrug for DMDZ in producing physical dependence in dogs.
在4只未用过药的犬单次静脉注射（2mg/kg）和口服（112.5mg/kg）哈拉西泮（HL）后，以及在5只长期给予HL（450mg/kg/天，每日4次）的成瘾犬中，研究了HL及其代谢产物去甲基地西泮（DMDZ）、奥沙西泮（OX）、3-羟基哈拉西泮（OH-HL）以及奥沙西泮结合物（OX-CONJ）和3-羟基哈拉西泮结合物（OH-HL-CONJ）的药代动力学特征。HL迅速代谢为主要代谢产物DMDZ，但在血浆和脑组织中检测到了相当水平的HL、OX和OH-HL。在血浆中检测到了高水平的结合代谢产物。HL及其非结合代谢产物的稳态血浆浓度可通过单剂量研究预测。在犬产生身体依赖性方面，哈拉西泮并非去甲基地西泮的简单前体药物。
