经典古方开心散抗抑郁活性成分的体内代谢特性研究

Traditional Chinese medicine (TCM) recipe is a complex system including multiple chemical constituent groups. Metabolism researches of TCM recipe have important significance in clarifying active substance of TCM and compatibility mechanism of TCM recipe. Based on previous works, this study take traditional anti-depressive compound recipe "Kai Xin San" as the key point to develop the metabolism research by cell, isolated organ, animal models and modern pharmacochemistry analytical methods such as LC/MS/MS. The metabolism of active components of Kai Xin San will be investigated to determine their metabolic pathway and enzyme. And then their original chemical constituents will be obtained. Furthermore the metabolism interaction of components from Kai Xin San will be also explored. This study will clarify the metabolic rules of multiple chemical constituent groups in Kai Xin San, make sure the effective substance and content control constituent of Kai Xin San, thus to put forward the possible lead compound and structure modification. This study may play important roles in several aspects as follows: to provide necessary evidence for quality standard and compatibility of TCM, offer new thoughts to pharmacokinetics studies of TCM recipe and improve the modernization of traditional Chinese medicine.

中药（复方）是多种化学成分群组成的复杂体系，中药复方代谢研究对于阐明中药有效物质基础、诠释复方配伍机制有重要意义。本项目拟在前期工作的基础上，以经典抗抑郁中药复方- - 开心散为切入点，采用细胞、离体器官和整体动物模型，借助LC/MS/MS等现代分析技术，以开心散主要成分的体内代谢研究为主，阐明代谢途径和代谢酶，进而获得其化学成分原形，并初步探索开心散各组分间药物代谢的相互影响，初步阐明开心散多种化学成分群的体内代谢规律，明确开心散的有效效应物质、含量控制组分，进而提出先导化合物与结构改造的可能性，为完善中药质量标准和配伍组方提供必要的科学依据，为复方中药药代动力学研究提供新的思路，推进中药现代化研究。

经典抗抑郁中药复方开心散由人参、远志、茯苓和石菖蒲四味药材组成，口服给药可显著改善模型动物的抑郁症状，本项目采用LC/MS/MS等分析技术，在整体动物模型和体外反应体系中对开心散及其主要成分的分布、代谢规律和代谢特点进行了研究。研究发现，在定志小丸提取物中共鉴定了97个化合物，其中50个化合物来源于远志，41个化合物来源于人参，6个化合物未归属单药来源，其中有3个化合物可能为新化合物；通过对比定志小丸指纹图谱与定志小丸灌胃给药动物后获得的含药血浆图谱，鉴定了正常大鼠含药血浆中的60个入血成分，抑郁大鼠含药血浆中的28个入血成分。作者通过GC-MS技术在定志小丸提取物中鉴定了10个挥发性成分，通过对比定志小丸GC-MS指纹图谱与定志小丸灌胃给药动物后获得的脑组织成分图谱，鉴定了正常大鼠和抑郁大鼠脑组织中的3个入脑成分。开心散的代谢途径较多，在胆汁、粪便、尿液和血浆中均有代谢产物。远志中的TESA经CYP3A4代谢可生成1个代谢产物，Tenuifoliside C，Tenuifoliside D，Telephiose A，Telephiose C和远志酮Ⅲ对CYP2E1有抑制作用。研究初步阐明了开心散多种化学成分群的体内代谢规律，明确了开心散发挥抗抑郁作用的物质基础，为完善开心散质量标准和配伍组方提供了必要的科学依据。