中药体内“三维药效物质基础”理论与方法学研究

On the basis of long-term research in the field of “herbal disposition and pharmacological mechanisms”, this project raises a new hypothesis of “three dimensional bioactive components” and “reverse pharmacokinetics, which indicates that there are different compositions of bioactive components at different time interval and in various organs/tissue/cells, and that the herbal compounds unable to be absorbed and/or inaccessible to the pathological sites may take effect via the regulation of endogenous bioactive metabolites. First, we intend to develop several key methodologies and strategies to address the critical challenges in the qualitative and quantitative analysis of herbal compounds/metabolites with trace/minor levels in biological matrixes, in clarifying the complicated metabolic network, and in the global analysis of endogenous bioactive metabolites. Focusing on “Sheng-Mai” prescription with widely confirmed clinical benefits, this project will elucidate the dynamic compositions in the circulation system and various targeting sites in the normal, ischemia/reperfusion, and the ApoE-/- treated with high fat diet model animals. Afterwards, the compounds/metabolites with appropriate exposure levels in certain tissues/organs/cells will be selected for pharmacological evaluation in a panel of appropriate in vitro models, from which the bioactive compounds targeting various tissues/cells can be proposed. Such bioactive compounds and their combinations will be subjected for further in vivo pharmacological evaluation and mechanistic assessment. Results obtained from this project is expected to provide innovative and generally applicable researching idea and methods for exploring the in vivo bioactive compounds of herbal medicines with physiological relevance and translational value, and may also provide theoretical and methodological insights to the discovery and development of modern combinatorial drugs.

基于长期的中药体内过程与作用机理研究积累，提出中药“体内三维药效物质基础”和“反向药代动力学”的科学假说，指出中药在生物体内不同时间段、不同组织器官/细胞内具有不同成分组成，不能有效吸收或不能到达病变部位的中药成分可通过调控内源活性物质，发挥“远程调控”作用。拟建立具有普适性的体内痕量/微量“非靶向”成分定性定量分析、中药复杂代谢网络解析以及内源活性分子的代谢组和蛋白质组学研究技术；以具有确切临床疗效的“生脉方”为主要研究对象，阐明其在正常、心肌缺血/再灌及ApoE-/-复合高脂模型动物体内血循环及多个靶部位的动态成分组成，优选在相应部位具有适宜曝露量的成分，设计心肌细胞、免疫细胞、肠道菌群等体外药效评价模型，确定作用于不同部位的有效成分，进而在整体动物模型确证单一成分及成分组合的药效作用与机理。为中药体内药效物质基础与机理研究提供新思路与方法，并为现代复方创新药物研发奠定理论方法基础。

本项目围绕 “中药在生物体内不同时间段、不同组织器官/细胞内具有不同成分组成，因而体内药效物质基础不同”这一关键科学问题，提出中药“体内三维药效物质基础”和“反向药代动力学”的科学假说，建立具有普适性的体内痕量/微量“非靶向”成分定性定量分析、中药复杂代谢网络解析以及内源活性分子的代谢组和蛋白质组学等研究技术；以具有确切临床疗效的“生脉方”等为主要研究对象，阐明体内药效物质基础与作用机理，为中药体内药效物质基础与机理研究提供新思路与方法，并为现代复方创新药物研发奠定理论方法基础。基于以上研究，本项目研究建立了一系列具有普适性的体内痕量/微量“非靶向”成分定性定量分析、中药复杂代谢网络解析以及内源活性分子的代谢组和蛋白质组学研究方法；以生脉方、人参皂苷、银杏叶提取物、水飞蓟宾、甘草酸等具有确切临床疗效的中药或有效成为为研究对象，在整体动物模型、体外细胞水平、分子水平分别确证了药效作用机理和潜在的药物作用靶标。本项目研究提出的新思路与新方法，为中药药效物质基础研究与作用靶标发现提供新理论和新方法。在Cell Metab等发表高水平SCI论文34篇，为中药体内药效物质基础与作用靶标研究提供了具有普遍借鉴意义的理论方法学体系。