Comprehensive study on the predition of drug disposition based on the physiological and anatomical mechanism.

本研究的目的是通过扩展最近发展的基于生理、解剖和生化机制的药物处置分析的生理模型的研究，建立一个定量预测药物代谢动力学变化的系统。这种药代动力学的改变包括物种差异、个体差异、年龄差异、昼夜节律的影响、病理状况、药物-药物相互作用的影响，以及药物配方的化学结构和性质的影响。现在真正的目标是完善系统来全面预测这些变化。例如，a)通过建立系统的数据库，建立一套扩大药代动力学研究的通用方法；b)通过细胞或膜泡系统研究药物在病理状态下或在多剂量方案下的处置机制，通过研究药物在肝脏和肾脏的转运机制，通过器官灌注系统的动力学研究，完成预测和诊断的方法。C)通过结合药物受体相互作用和药代动力学的研究来预测药物作用的开始和抵消。这个小组由13名成员组成，并继续研究了2年（1985年和1986年）。这项研究产生了许多原创的发现和重要的结果。特别值得一提的是以下研究：基于生理转运机制的多肽药代动力学分析，基于分子机制的抗菌素药代动力学预测和药物药理作用的定量预测，以及基于生理机制的药物在肾脏和肝脏转运代谢过程的动力学分析，特别是：利用离体肝细胞进行共轭反应和氧化反应代谢酶的不均匀分布，建立肾基底外侧和刷边膜泡的分离，并利用这些膜泡系统进行主动转运过程的动力学分析。每年2月在东京召开会议，并进行了积极的讨论，这似乎极大地刺激了这个项目。少

The aim of this study is to make a system which predict quantitatively the various alterations in the pharmacokinetics by expanding the study of physiological model recently developed for the analysis of drug disposition based on the physiological, anatomical, and biochemical mechanisms. This alterations in pharmacokinetics include the species difference, interindivisual difference, age difference, effect of circadian rhythm, pathological condition, drug-drug interaction, in addition, effect of chemical structure and character of pharmaceutical formulation. It is now a true objective to complete the system to predict these alterations comprehenssively. For example, a) to establish a general methodology in scaling-up the pharmacokinetics by making a data bank systematically, b) to make clear the mechanisms of drug disposition in pathological condition or in multiple dosage regiments and to complete the methodology of prediction and diagnosis by studying the mechanism of drug transport i … More n liver and kidney using cell or membrane vesicle system and by kinetic study using organ perfusion system, c) to predict the onset and offset of drug action by combining the studies on both drug-receptor interaction and pharmacokinetics. This group consisted of 13 members and continued the study for 2 years (1985 and 1986). This study has produced many original findings and important results. Special mention should be made on the following study: the analysis of pharmacokinetics of peptides based on the physiological transport mechanism, the prediction of the pharmacokinetics of antimicrobials based on the molecular mechanism and quantitative prediction of the pharmacological effect of these drugs, in addition, kinetic analysis of the process of transport and metabolism of drugs in kidney and liver based on physiological mechanism, especially, uneven distribution of the metabolic enzymes of conjugative ractions as well as oxidative reactions using isolated hepatocytes, and the establishement of the isolation of the baso lateral and brush border membrane vesicles from kidney and the kinetic analysis of active transport process using these membrane vesicle system. Meeting was held in every February in Tokyo and active discussions were made, which seemed to stimulate this project extremely. Less