Srivastava K, Hatanaka T, Aiba T, Katayama K, Koizumi T
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Biol Pharm Bull. 1999 Jun;22(6):627-32. doi: 10.1248/bpb.22.627.
The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a benzodiazepine, oxazepam, in renal dysfunction rats. For the in vivo experiment, normal and renal dysfunction rats were given 40 mg/kg of oxazepam as the bolus dose. A quantitative electroencephalographic (EEG) method was used as the surrogate measure of the pharmacological response. The oxazepam concentration in plasma and cerebrospinal fluid (CSF) was assayed by the HPLC method. The steady-state volume of distribution and clearance based on total and unbound plasma did not change in renal dysfunction rats. Amplitude changes in the EEG induced by oxazepam in normal and renal dysfunction rats were characterized by a log-concentration response model or sigmoidal Emax model. The pharmacodynamic parameters from these models were not altered in renal dysfunction. In in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, the oxazepam-induced effect was not potentiated by the plasma dialysate from renal dysfunction rats. Thus, it was suggested that the brain sensitivity to benzodiazepines was not altered in renal insufficiency.
本研究旨在探讨苯二氮䓬类药物奥沙西泮在肾功能不全大鼠体内的处置特征和药效学。在体内实验中，正常大鼠和肾功能不全大鼠均给予40mg/kg奥沙西泮的单次静脉推注剂量。采用定量脑电图（EEG）方法作为药理学反应的替代指标。通过高效液相色谱法测定血浆和脑脊液（CSF）中的奥沙西泮浓度。基于总血浆和游离血浆计算的稳态分布容积和清除率在肾功能不全大鼠中未发生变化。正常大鼠和肾功能不全大鼠中奥沙西泮诱导的脑电图振幅变化采用对数浓度反应模型或S形Emax模型进行表征。这些模型的药效学参数在肾功能不全时未发生改变。在γ-氨基丁酸（GABA）-苯二氮䓬受体复合物的体外结合研究中，肾功能不全大鼠的血浆透析液并未增强奥沙西泮诱导的效应。因此，提示肾功能不全时大脑对苯二氮䓬类药物的敏感性未发生改变。
