针对中药研究领域急需解决的药代动力学与药效动力学关联研究比较薄弱的问题，以中医药理论的整体观、动态观和辩证观为指导，本项目提出了基于Top-Down-Top模式的中药体内代谢物质组群与药效关联性研究的方法。研究内容为：以定志小丸为治疗药物，阿尔兹海默症(AD)大鼠为模式动物，首先，在整体动物水平，通过药物与机体相互作用研究，明确药物作用于机体的相关作用靶标和机体对药物进行体内处置后的体内化学物质组群；其次，利用计算机模拟及超滤质谱筛选方法，从体内化学物质组群中筛选得到作用于不同靶标的多个体内活性物质组群；最后，对每个活性物质组群分别进行叠加整合药代动力学研究(PK)，针对不同靶标，选取各个代谢时间点的活性物质组群进行药效动力学研究(PD)，并进行PK-PD关联性分析，最终阐明定志小丸治疗AD的药效物质基础和作用机制。本项目研究成果将为解决中药体内代谢物质组群与药效关联性研究提供一种新策略。

The study of the correlations between pharmacokinetic and pharmacodynamic is relatively limited, which is an urgent problem in the medical research field. In order to solve this problem, we propose a system analysis method based on Top-Down-Top mode for the study on the correlation between the in vivo metabolites groups of traditional Chinese medicine and effectiveness. In this project, the Dingzhixiaowan for treatment of Alzheimer's disease (AD) is selected as the study object. Firstly, the drug targets and in vivo chemical group will be clarified through animal/drug interaction studies at the whole animal level. Secondly, screen the in vivo active substance group acted on multiple targets from the in vivo chemical substances group by using the docking and molecular dynamic simulations and ultrafiltration-mass spectrometry method. Finally, the integrated pharmacokinetics study, pharmacodynamic study and pharmacokinetic-pharmacodynamic correlation studies will be carried out to clarify the in vivo pharmacodynamic substances and mechanism of action of Dingzhixiaowan for the treatment of AD. The results of this project will provide a new strategy for the study on the correlations between the in vivo metabolites groups of traditional Chinese medicine and effectiveness.