基于药物相互作用的元胡止痛方配伍分子机制及其PK-PD关联性研究

项目名称： 基于药物相互作用的元胡止痛方配伍分子机制及其PK-PD关联性研究

项目编号： No.81473414

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 许海玉

作者单位： 中国中医科学院中药研究所

项目金额： 71万元

中文摘要： 揭示方剂配伍规律是中药现代研究的关键科学问题之一。本项目选用元胡止痛方为模式方剂，在前期通过化学指纹-代谢指纹-药效靶标三维模型研究明确了元胡止痛方的药效物质基础及其作用机制，并发现延胡索与白芷配伍引起主要活性成分（生物碱类和香豆素类）的药代动力学特征发生变化，存在明显的药物代谢相互作用。以此为基础，在本项目中，抓住药物吸收和代谢两个关键环节，采用Caco-2细胞模型和肝药酶（CYP 450）代谢模型，从转运体和药物代谢酶探讨元胡止痛方配伍引起药物代谢相互作用的分子机制；然后，进行药效学研究，采用慢性压迫损伤性（CCI）模型，以定量代谢组学为手段，探讨元胡止痛方不同配伍对疗效的影响；并通过数据建模探讨元胡止痛方的多组分网络靶点效应PK-PD结合模型建立，并通过生物信息学数据挖掘，从方剂活性物质-体内药物代谢-药物效应标志物三维模型探讨方剂配伍增效减毒的科学内涵。

中文关键词： 药物-药物相互作用；代谢组学；方剂配伍机制；药物代谢酶；药物转运体

英文摘要： It is very critial to uncover the molecular mechanism of the compatibility of Traditional Chinese Medicine(TCM). In this study, Yuanhu Zhitong prescription is regarded as typical prescription to study it. In our previous research, our teams have carried out organized and consistent studies in an attempt to shed light on the active constituents and action mechanisms of YZT based on chemical fingerprint, metabolic fingerprints and network pharmacology. However,the drug-drug interaction between Yuanhusuo and Baizhi were found in the pharmacokinetics of YZP and the pharmacokinetic profiles of mainly active components were changed from the compatibility. Therefore, the mechanism of drug-drug interaction underlying the compatility would be firstly performed based on the intestinal absorption using Caco-2 cell and the metabolism using CYP 450 enzymes.Then, the rats with chronic constrictive injury (CCI) are used to evaluate pharmacodynamics of Chinese prescription and single herbs. In addition, biomarkers of chronic pain might be discovered by quantitative metabonomics and appied to build the PK-PD model of YZP by data mining. In conclusion, the three-dimensional model of active components,the ADME process in vivo and the effective biomarkers would provide new insight on a deeply understanding of the molecular mechanism of the compatibility of TCM.

英文关键词： drug-drug interaction;metabonomics;Compatibility of TCM;P450 metabolic enzyme;Drug transporters