Tanaka E, Ishikawa A, Misawa S
Institute of Community Medicine, University of Tsukuba, Ibaraki-ken, Japan.
Pharmacol Toxicol. 1994 Sep-Oct;75(3-4):150-3. doi: 10.1111/j.1600-0773.1994.tb00338.x.
We investigated the possibility of predicting liver damage from changes in the serum concentrations of caffeine (10 mg/kg), lidocaine (4 mg/kg) and trimethadione (4 mg/kg), which are metabolized catalysed by different cytochrome P450 (P450) and/or are dependent on blood flow, in rats with carbon tetrachloride (CCl4: 0.25 ml/kg)-induced liver injury using a strategy referred to as a "cocktail" study. These 3 probe drugs were simultaneously administered intravenously. The half-lives (t1/2) of caffeine, lidocaine and trimethadione were significantly longer in the CCl4-treated group than in oil-treated controls, but no significant differences were observed in mean apparent volumes of distribution (Vd). Serum total body clearance (CL) values of all three drugs were markedly reduced in CCl4-treated animals. In rats with liver damage, the production of 3 metabolites (theobromine, paraxanthine and theophylline) of caffeine in addition to the only metabolite (dimethadione) of trimethadione after intravenous administration of probe drugs were significantly reduced compared to those of controls. These findings suggest that each probe drug, metabolized by different or partially overlapping P450, is useful in evaluating drug-oxidizing capacity in liver disease.
我们采用一种被称为“鸡尾酒”研究的策略，在四氯化碳（CCl4：0.25 ml/kg）诱导肝损伤的大鼠中，研究了根据咖啡因（10 mg/kg）、利多卡因（4 mg/kg）和三甲双酮（4 mg/kg）血清浓度变化来预测肝损伤的可能性，这三种药物分别由不同的细胞色素P450（P450）催化代谢和/或依赖于血流。这三种探针药物通过静脉同时给药。在CCl4处理组中，咖啡因、利多卡因和三甲双酮的半衰期（t1/2）显著长于油处理对照组，但平均表观分布容积（Vd）未观察到显著差异。在CCl4处理的动物中，所有三种药物的血清总体清除率（CL）值均显著降低。在肝损伤大鼠中，静脉注射探针药物后，咖啡因的3种代谢产物（可可碱、副黄嘌呤和茶碱）以及三甲双酮的唯一代谢产物（二甲双酮）的生成量与对照组相比显著减少。这些发现表明，每种由不同或部分重叠的P450代谢的探针药物，在评估肝脏疾病中的药物氧化能力方面是有用的。
