中药复杂组群代谢与药效机制桥接新理论及方法研究

Nature medicine is tended to produce a variety of metabolites by gut flora and enzymes. Active metabolites are important pharmacological material basis in vivo, as well as a source for new drug discovery. However, there are difficulties for explaining metabolic properties with classic drug metabolism theories due to the characters of nature medicine clusters. According to the foundation of research, we propose “polymetabolism” theory in this project, including classical phase I/II metabolism, quantitative metabolism and internalization metabolism. Based on the general method establishment of nature medicine complex cluster metabolites preparation and analysis, and using “Sheng Mai Fang” as a model, we plan to reveal the metabolic pathways, laws and mechanisms of major components in vivo and in vitro to prove the “polymetabolism” theory, meanwhile focusing on neuroendocrine-immune regulation, using mechanism based PK/PD bridging method to find the pharmacodynamics properties of metabolics as well as revealing influence of this metabolic variation on cardiac-cerebral vascular disease therapeutic effect of “Sheng Mai Fang”. Our research is of significant scientific values on evaluating the contributions of natural medicines metabolism to the total therapeutic effect and metabolites-based new drug discovery.

中药成分群易在肠道菌群及各种代谢酶的作用下，生成复杂多样的代谢产物；活性代谢产物是中药发挥整体药效作用的重要体内物质基础，也是新药发现的重要来源。由于中药成分的组群特性，经典化学药物代谢理论和技术难以概述和阐释中药代谢特性。本项目基于良好的前期基础，提出中药“多向代谢”（polymetabolism）的新理论，包括经典的I/II相代谢、量变代谢和内化代谢三种反应类型，拟以生脉方为模型方剂，在建立中药复杂组群代谢产物分析、制备等共性关键技术的基础上，深入揭示生脉方主要组分群的体内外代谢途径、规律和机理，确证本项目提出的“多向代谢”新理论；聚焦神经内分泌免疫调节作用，通过基于机制的药动/药效桥接研究，探讨各类代谢产物的药效作用特点，揭示各类代谢产物变化对生脉方治疗心脑血管疾病的影响。项目研究对于阐明中药代谢对整体疗效的贡献和基于活性代谢产物的创新药物发现具有重要科学价值。

本项目基于中药成分体内复杂代谢过程以及中药活性成分组群特性，创新性的提出中药“多向代谢”理论，阐明中药成分在体内代谢可分为经典的I/II相代谢、量变代谢以及内化代谢。项目研究以建立中药代谢研究共性关键技术和方法为切入点，建立了多种体内中药代谢产物组的定量表征、代谢组群-药效桥接鉴定技术，提出“代谢谱效”关系研究策略和方法；随后借助多向代谢新理论以及方法学，以五味子、生脉方、银杏叶、人参等中药经典方剂或药物作为研究模板，针对中药活性成分群的多向代谢，探讨主要成分群的代谢特征与药效的对应规律，揭示中药药效物质基础-多向代谢调控-药效关键环节与靶标的科学内涵。最后以生脉方为模板，探索生脉方代谢对其治疗心脑血管疾病整体药效作用的影响，发现具有开发前景的先导化合物。期间发表高水平SCI论文15篇，丰富和完善了中药成分体内多向代谢特征理论，并为中药药效-机理研究提供范例研究模板。