Fundamental Studies on Population Pharmacokinetics of Alcohol and Alcohol-Drug Interaction

开展了酒精的群体药代动力学及酒精与药物相互作用的基础研究。本文首先利用米氏消除动力学模型研究了酒精代谢动力学分析的技术问题。将普通最小二乘法（OLS）与贝叶斯最小二乘法（BLS）进行了比较。用OLS法估计参数值时，V<max>_m与β值、V_m<max>与K_m值之间存在相关性。这些结果表明，OLS法的一条直线拟合不适用于Michaelis-Mentan型消除动力学分析。其次，研究了线粒体乙醛脱氢酶抑制剂氰胺抑制乙醇代谢的药代动力学机制。结果表明，氨腈处理降低了土壤的V<max>值，而K_m值没有变化。我们的研究结果对应于乙醇代谢的非竞争性抑制。这一结果被认为是酒精与药物相互作用的一个例子。

Fundamental studies on population pharmacokinetics of alcohol and alcohol-drug interaction were conducted. At first, the technical problems of the pharmacokinetic analysis of alcohol disposition were studied using the Michaelis-Menten elimination kinetics models. The ordinary least-squares (OLS) method was compared with the Baysian least-squares (BLS) method. Correlation between the V_<max> and beta values, and between the V_<max> and K_m values, was seen when the parameter values were estimated by the OLS method. These results suggested that one-line fitting by the OLS method was not adequate for Michaelis-Mentan-type elimination kinetics analysis.At second, the pharmacokinetic mechanism of the inhibition of ethanol metabolism by cyanamide, an inhibitor of mitochondrial aldehyde dehydrogenase, was studied. As a result, the estimated V_<max> values decreased by cyanamide treatment, whereas the K_m value did not change. Our results correspond to a noncompetitive-like inhibition of ethanol metabolism. This result is thought to be an example of alcohol-drug interaction.