药物相互作用（DDI）一直是新药研发失败的重要原因，而利用体外代谢数据预测体内DDI，其可靠性和准确性尚不尽人意。为克服这一困难，我们试图建立一种体外动态Bio-PK/PD系统，结合PBPK模型预测体内CYP介导的药物相互作用。具体研究内容包括：（1）以人肝微粒体水凝胶为代谢载体，引入微透析采样技术，构建Bio-PK/PD代谢系统；（2）以经典底物及抑制剂为模型药物获取体外代谢参数，利用Matlab分别建立可逆性和机制性失活抑制的DDI动态模型；（3）结合PBPK建模所需的理化参数和体外代谢数据，进一步验证体外模型的准确性，模拟趋于真实的体内DDI行为；（4）以抗肿瘤候选化合物千层纸素（OA）为实例，利用该系统研究其代谢及潜在DDI，同时考察CYP基因多态性对其体内DDI的影响。我们拟建立一套能够真实反映体内DDI行为的体外动态模拟系统，将为降低药物研发风险、提高成药性提供全新思路和方法。

Drug-drug interaction (DDI) has always been key reason for the failure of drug development. In vitro assessment of metabolism data designed to evaluate potential DDI is influensed by its reliability and accuracy. Based on the results of our previous study on Bio-PK/PD system utilizing rat microsomes, we will develop an in vitro dynamic DDI simulation system. In this system, we will lock the human microsomes in the hydrogel of 3D structure, and microdialysis sampling technique is applied to monitor the drug concentrations in the hydrogel. We focuses on the study of the reversible inhibition and mechanism-based inactivation. In vitro model is built by Matlab, and physiologically based pharmacokinetic (PBPK) modeling technology is used to predict and simulate the in vivo DDI and validate the in vitro model. The natural antitumor product Oroxylin (OA) is a very promising candidate compound. But there is no study on DDI of OA. We will study the potential DDI of OA and the genetic polymorphism of CYP contributing to DDI of OA using Bio-PK/PD simulation system combined with PBPK modeling. Ultimately, we will develop a set of in vitro dynamic model which is highly correlated with in vivo DDI. This system will provide new ideas and methods for decreasing risk of drug development and increasing druggability.