三七皂苷体内代谢产物与药效关联性研究

Traditional Chinese medicines are dosed mainly by oral administgration and the glycosides existing in many TCMs as principle bioactive components are sbsorbed in to blood after biotransforming into their corresponding aglycons or secondary glycosides by intestinal bacteria. The aglycons or secondary glycosides may further be activated to produce active metabolites by liver micrisome enzymes to play effecy. Therefore, the identification of metabolites and understanding the possible relevance of the metabolites and the efficacy is of important significance for the interpretation of the traditional Chinese medicine and their underlying mechanisms, quality control, and discovory of new drugs or candidates.. The precent project deals with the pharmacokinetics and pharmacodynamics syudy of the representative notoginsenosides, isolated from Panax notoginseng by use of pharmacokinetics, pharmacology, chemical biology and other means to identify the metabolites in vivo after oral administration of the saponins, discover the relevance of the metabolites and pharmacodynamics, reveal the potency of the metabolic substances produced in effective exposed amount. .The synergistic agonistic or antagonistic effects of the prodrug of saponins and their biotransformed metabolites on platelet P2Y12 receptor and structure-activity relationship of the different types of skeletones and glucosidation patterns of the saponins on the target will also be compared and elucidated to explain the regulatory effect of Panax notoginseng for its bidirectional effects of hemostasis and promoting blood circulation. .In a word, this project will provide evidence-based mechansms for disclosing the active components of Panax notoginseng and and its broad spectral activities in clinical application of both the crude drug and Notoginseng-containing fishished products as well as other saponins-containing medicinal herbs.

中药以口服为主，很多中药中含有的苷类成分多在肠道或肝脏发生生物转化，以次级苷或苷元的形式吸收入血，从而发挥药效。因此，鉴定代谢产物，并解释代谢产物与药效的关联性，对于诠释中药的物质基础、作用机理、质量控制、创新药物研发均具有重要意义。本项目在前期研究的基础上，以代表性三七皂苷为对象，综合运用药代动力学、药理学、化学生物学等手段，分析、鉴定口服给药后的体内代谢产物，研究其体内代谢产物与药效的关联性，揭示代谢产物体内暴露量对药效的贡献度;以血小板P2Y12受体为主要作用靶点，研究不同母核、不同糖基化模式的皂苷及其代谢产物对受体的生物效应差异，并探讨其在有效体内暴露剂量下，三七皂苷原型及其代谢产物止血/活血的协同或拮抗作用及其分子机制, 为诠释中医药理论、源于中药的创新药物研发和科学质量控制奠定基础，也为其它含苷类中药复杂体系的解析提供借鉴。

本项目主要对三七根、根茎及茎叶进行了皂苷类化学成分表征和单体皂苷的分离制备，从不同途径分离制备三七皂苷及其代谢产物，为代谢、药理、质量控制研究提供对照物质；对部分微量皂苷（包括体内代谢产物）进行了生物转化与合成生物学研究；对代表性皂苷成分如三七皂苷Fc、R1、人参皂苷Rb1体内代谢、分布、排泄等体内过程规律进行了研究，包括新代谢产物的鉴定；对不同类型皂苷及与核心功效相关的体内代谢产物进行了抑制血栓生成、抗脑卒中、改善深静脉血栓、促糖尿病伤口愈合及减轻炎症性肠病等多方面药理作用开展了广泛深入的研究；上述研究为诠释三七药效物质基础与作用机理、弘扬祖国医药学理论与实践及进一步开发利用三七药用资源提供了参考。此外作为项目拓展研究，还采用原位色谱-质谱、在线二维多中心切割液相色谱法，鉴定出三七不同药用部位、生熟不同加工方法、不同制剂工艺产品中皂苷类成分的差异，并据此制定了行业、企业内控标准；并鉴于三七皂苷在胃酸中降解严重，而在肠道保留的药动学特点，设计了总皂苷多重自乳化给药体系，显著提高三七总皂苷的口服生物利用度，为三七皂苷的新药研发、临床应用提供了新的策略。已按计划完成了预期计划及目标，阐明三七皂苷的时－效、构－效、组－效关系及其与体内代谢的相关性，并发现了三七皂苷新的药理活性及作用机制。在上海中医药大学与企业共建“三七研究中心”，定位于合作开展三七系列新药产品的研发、资源可持续利用，为三七皂苷类成分新药开发、科研成果转化奠定基础，亦为三七及其制剂的标准提升提供了技术依据，服务于健康产业发展。本项目在中期考核及结题汇报评估中均获得优秀。研究成果已发表论文30篇，其中SCI收录24篇，中文核心期刊论文6篇；获专利授权9件。培养研究生13名，其中博士生10名，博士后8名；青年学术骨干4名。作为本项目的延申，获NSFC重点国际（地区）合作交流项目1项，青年基金4项。