体外动态Bio-PK/PD系统结合PBPK模型预测体内CYP介导药物相互作用的研究

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.

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。

鉴于目前体外代谢模型的局限性，本课题建立了一种新型的Bio-PK/PD体外动态代谢系统，结合PBPK模型预测药物体内药物代谢动力学和药物相互作用(DDI) 。首先在Bio-PK/PD循环灌流装置基础上引入透析采样技术，成功构建Bio-PK/PD体外动态代谢系统；在此基础上，以人肝微粒体酶探针底物为模型药物，考察它们在该系统中的代谢行为，结合生理药代模型验证该系统的可行性。结果发现和传统孵育相比，该系统结合PBPK拟合结果更接近体内处置情况。之后，以经典底物及抑制剂为模型药物，利用Matlab建立抑制的DDI动态模型，结合生理药代模型进一步验证了Bio-PK/PD体外动态代谢系统在DDI研究中的可行性。同样地，和传统的孵育体系的比较，该系统拟合的结果更接近人体内真实的DDI情况，并将其成功应用于预测临床上安非他酮介导的DDI。同时，我们在人肝微粒体-水凝胶体系引入效应细胞腔室，进一步研究了药物代谢后药效及毒性的变化。以黄芩素为实例，发现代谢后对细胞的活性以及毒性结果与文献报道的结果一致，成功预测了黄芩素代谢后的抗肿瘤作用，并成功应用于的千层质素和汉黄芩素的药效及毒性研究。最后我们进一步在已构建的Bio-PK/PD体外动态代谢系统基础上合并透析注射泵装置，并以UGT经典底物及抑制剂对改进装置在药代和DDI的应用中进行了验证，结果表明和传统的UGT孵育体系相比，该系统结合PBPK预测结果和人体内DDI结果更接近。综上，我们成功构建了Bio-PK/PD体外动态代谢系统，并综合考察了该系统在药物代谢动力学、DDI以及药效，毒性中预测中的应用。该系统更加真实地反应药物在体内的处置和作用过程，为候选化合物的筛选提供了新的思路和方法。