Matsumoto H, Fujimiya T, Fukui Y
Department of Legal Medicine, Kyoto University Faculty of Medicine, Kyoto 606-01, Japan.
Alcohol Alcohol Suppl. 1994;29(1):15-20.
Ethanol elimination in rats following bolus intravenous administration (0.5, 1, 2, 3 g/kg body weight) was investigated with and without pyrazole pretreatment. Elimination time was significantly longer in the pyrazole-pretreated group than in the control. Simultaneous multilines fitting of two-compartment models to the ethanol concentration-time courses proved that the two-compartment model with Michaelis-Menten elimination kinetics was optimum to the curves in both groups. the V(max) value (0.41 +/- 0.05 mg/ml/hr) in the pyrazole-pretreated group was significantly lower than that (0.70 +/- 0.03 mg/ml/hr) in the control. The K(m) value (1.44 +/- 0.12 mg/ml) in the pyrazole-pretreated group was significantly higher than the control (0.07 +/- 0.01 mg/ml), similar to the in vitro value in hepatic alcohol dehydrogenase (ADH). This higher K(m) value in the pyrazole-treated group than the in vitro value in the microsomal ethanol oxidizing system (MEOS) suggests that pyrazole-insensitive pathways may involve pathways other than MEOS. The first-order elimination rate from the two-compartment model with parallel first-order and Michaelis-Menten kinetics was a very low value of 10(-5)min(-1) ,which shows that a pathway with a higher K(m) than blood ethanol concentration does not contribute to in vivo ethanol elimination. The relative contribution of the pyrazole-sensitive pathway calculated from the ratio of total clearance in two groups was 83% at a low ethanol concentration of 0.5 mg/ml and 60% at a high concentration of 5.0 mg/ml. The K(m) value (0.02 mg/ml) from fitting the double Michaelis-Menten model is similar to that in vitro in ADH3. These findings suggest that the ADH3 pathway plays a major role in ethanol elimination.
在有或没有吡唑预处理的情况下，研究了大鼠静脉推注给药（0.5、1、2、3 g/kg体重）后乙醇的消除情况。吡唑预处理组的消除时间明显长于对照组。对乙醇浓度-时间过程进行两室模型的同时多线拟合证明，具有米氏消除动力学的两室模型最适合两组的曲线。吡唑预处理组的V(max)值（0.41±0.05 mg/ml/hr）明显低于对照组（0.70±0.03 mg/ml/hr）。吡唑预处理组的K(m)值（1.44±0.12 mg/ml）明显高于对照组（0.07±0.01 mg/ml），与肝醇脱氢酶（ADH）的体外值相似。吡唑处理组的K(m)值高于微粒体乙醇氧化系统（MEOS）的体外值，这表明吡唑不敏感途径可能涉及MEOS以外的途径。具有平行一级和米氏动力学的两室模型的一级消除率非常低，为10(-5)min(-1)，这表明K(m)高于血液乙醇浓度的途径对体内乙醇消除没有贡献。根据两组总清除率的比值计算，在低乙醇浓度0.5 mg/ml时，吡唑敏感途径的相对贡献为83%，在高浓度5.0 mg/ml时为60%。通过双米氏模型拟合得到的K(m)值（0.02 mg/ml）与ADH3的体外值相似。这些发现表明，ADH3途径在乙醇消除中起主要作用。
