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新近开发的基于生理、解剖和生化机制的药物处置分析的生理模型的研究，建立一种定量预测药物动力学各种变化的系统。药代动力学的改变包括物种差异、个体间差异、年龄差异、昼夜节律的影响、病理状态、药物相互作用以及药物的化学结构和制剂性质的影响。现在，完成全面预测这些变化的系统是一个真正的目标。例如，a)通过系统地建立数据库来建立放大药代动力学的通用方法学；b)通过研究药物转运机制i…来阐明药物在病理条件下或多剂量方案中的处置机制以及完善预测和诊断的方法学。C)结合药物受体相互作用和药代动力学研究，预测药物作用的起效和消退。该小组由13名成员组成，并持续了两年的研究(1985和1986)。这项研究产生了许多原创性的发现和重要的结果。重点开展了以下研究：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药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的转运和代谢过程的动力学分析，特别是结合体代谢酶的不均匀分布以及利用分离的肝细胞进行氧化反应的研究，以及从肾脏分离基侧和刷状缘膜囊泡的建立以及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，进行积极的讨论，这似乎极大地刺激了这一项目。较少

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