临床上常利用五酯胶囊（WZC）的保肝作用来缓解免疫抑制剂他克莫司（TAC）的肝毒性，并用来降低TAC剂量以节省费用。但是影响两者之间药物相互作用（DDI）个体差异的很多因素，特别是CYP3A5基因型，其影响还不清楚。因为中药的多组分，按传统思路系统研究中药和西药的相互作用非常困难，特别是如何利用体外数据定量预测体内的DDI和定量分析各组分的贡献。本项目试图应用生理药动学（PBPK）建模并结合主成分"敲除/敲入"思路来定量地预测WZC和TAC的药动学DDI。PBPK用于预测4个WZC主成分对DDI的贡献，而从整体上评价主成分敲除后其它成分对DDI的影响。用大鼠来帮助获取人PBPK模型建立和优化的策略，而从文献获取验证人模型的临床数据。最终利用建立的人预测模型替代临床试验考察CYP3A5基因型等因素对WZC和TAC的DDI的影响，为临床确定最佳安全合并用药方案或优化临床研究提供依据。

Wuzhi capsule, which is composed of ethanolic extract of Schisandra sphenanthera Rehd.et Wils, has been reported to be co-medicated with tacrolimus to reduce the dosing amount of the immunosuppressant . However the factors contributing to the drug-drug interaction (DDI) between these two drugs have not been sufficiently elucidated, particularly the genetic polymorphism of CYP3A5, which plays an important role on the clinical DDI findings. The complex components of Chinese Traditional Medicine (TCM) make it extremely difficult to systematically investigate their DDI potential, especially to predict the in vivo TCM DDI possibility based on in vitro data and to further quantitatively determine the contribution of each individual component in TCM. The present project focuses on the study of the DDI between Wuzhi capsule and TAC using the most popular physiologically based pharmacokinetic (PBPK) modeling technology and the "knock-in/knock-out" strategy. Specifically, by utilizing the commercially available PBPK software-Simcyp and GastroPlus, the PBPK modeling is employed to evaluate and predict the exact contribution of 4 principal components in Wuzhi capsule to the overall DDI potential. Meanwhile these 4 components are knocked out to obtain the matrix components. Their individual contribution to DDI will be evaluated both in vitro and in vivo. Subsequently the quantitatively obtained influence of the 4 principal components will be scaled to calibrate and predict the systematic DDI potential of Wuzhi capsule in clinical settings. The rat model will be utilized to establish and optimize the PBPK strategy for humans. Finally the optimized human prediction model of DDI will be utilized to investigate the effect of CYP3A5 polymorphism and other factors on DDI between Wuzhi capsule and tacrolimus. The research investigation of this project will provide key insights into the rationales of future clinical research on this topic. The gained knowledge will also guide the optimal combination use of Wuzhi capsule and tacrolimus based on strong scientific foundations.