基于生理药动学模型的异丙嗪在模拟失重机体内的处置机制研究

Classical compartmental models are usually used in the study on pharmacokinetics in space, they are very poor for physiological interpretation. It is difficult to predict kinetic profiles when the underlying physiology changes in weightlessness，which can make astronauts in potential dangers. Physiological based pharmacokinetic ( PBPK )models aim to describe the drug disposition within the body based on the physiological parameters, the particular and physiochemical properties. PBPK models are mathematical models to conduct extrapolations of the kinetic behavior of drugs with regard to dose, route, species and various physiological conditions. This project is the first application of PBPK models in the pharmacokinetic study under simulated weightlessness. The quality differential equations are established by determining the physiological parameters, particular properties of drug and its metabolites, distribution in tissues or organs and pharmacodynamic parameters. The PBPK models of rats under ambulatory and tail-suspended condition are established. The project aims to build the individual administration schemes for astronauts based on the extrapolation of dosage and routes of administration from rat in normal gravity to rat in simulated weightlessness. At last, the extrapolations from rat to human are realized. We endeavor in making beneficial discover of drug research in space to ensure the drug for astronauts safe and effective.

目前航天药代动力学研究采用经典房室模型计算参数，缺乏不同生理状态的关联分析，失重导致机体生理功能改变时难以准确预测动力学参数，给指导航天员安全用药埋下隐患。生理药动学（PBPK）模型是以机体生理参数、药物的理化性质和特异性参数为基础，从整体效应阐明药物在机体内的处置过程，可实现不同生理状态和种属间推算，弥补经典房室模型的不足。本项目首次将PBPK模型应用到失重状态下的药代动力学研究。以航天抗运动病首选药物异丙嗪作为模型药，测定机体生理学参数、药物及其代谢产物的特异性参数、组织或器官药物分布、药效学参数等，建立质量微分方程组，建立正常和尾吊大鼠的PBPK模型，进行比较分析，在实现从正常大鼠到模拟失重大鼠用药剂量和给药方式推算的基础上，实现从动物到人，以及从地面到失重状态下航天员用药的计算，建立宇航员的个体用药方案，为航天药物研究进行有益的探索，确保航天员用药安全有效。