基于“丸剂特征-整合药动-机体应答”的附子理中丸“去性存用”作用机制研究

“Pill release slowly with a long-time efficiency” is the essence of TCM pills theory which reflect that pills can eliminate toxicity and remain efficacy. Toxic herbs were often made into pills to eliminate the toxicity as well as remain its efficacy. The transformation and function mechanism of "effective but toxic" TCM have always been the key object in TCM basic researches but they’re also difficult to be studied. Fuzi-lizhong pill, a classical prescription for warming middle-jiao and tonifying spleen, is without toxicity and its preparation process is to smash herbs and made pills. However, the monarch herb in the prescription is aconite, which is a typical "effective and toxic" TCM. In previous study, we found that the dissolution process of the main components in Fuzi-lizhong pill continuing as long as 48 hours in vitro, which shows the characteristic of “pill release slowly with a long-time efficiency”. To propose hypothesis: Fuzi-lizhong pill has the peculiarity of “removing the drastic and toxic substance as well as keeping its efficacy” because of the characteristic of pills dosage form. This peculiarity is expressed though the basic constituent, pharmacokinetics and the body’s efficacy response. In this project, LC- MS/MS technique combined with serum pharmacochemistry is applied to identify the efficacy constituent, which has moved into blood. The specific constituents will be found and considered as the basic components of the “eliminating toxicity but remaining efficacy" peculiarity. Besides, PK-markers will be selected based on the efficacy constituent, and their pharmacokinetics process will be researched though the perspective of dose-time-toxicity/efficacy. Finally, the spleen yang deficiency body’s response section including biological signals feedback, gastrointestinal motility regulation and toxicity of viscera will be researched in order to understand the mechanism of the peculiarity. In sum, this project will reveal the mechanism that toxicity and efficacy can be regulated by dosage form, and will provide a new idea for the fusion of the TCM pills theories and the modern technologies.

“丸者缓也”是中药丸剂实现减毒存效的理论精髓之一，自古大毒者多入丸剂以去其毒峻之性，存其疗效之功，毒效双重中药的作用机制一直是中药基础研究的重难点。温中健脾经方附子理中丸，君药附子辛热燥烈，毒效双重，然而全方打粉制丸，制剂却不显毒燥之性。课题组前期发现：附子理中丸主要成分体外溶出行为持续48h，有“丸者缓也”剂型特征。故提出假说：丸剂剂型特征赋予附子理中丸“去毒燥之性而存温中之用”特性，并体现在效应物质基础及机体药动与药效应答环节。本项目拟采用LC-MS/MS桥接血清药化方法明确制剂的效应标志成分，寻找成分与含量特异性以探明“去性存用”物质基础；基于效应物质优选PKmarkers，从多成分量时毒/效整合药动学角度，以及脾阳虚模型生物信号反馈、胃肠动力调节及脏器毒性表现环节，探明制剂“去性存用”作用机制，从而揭示剂型对毒/效的多维调控机制，为中药丸剂理论与现代技术的融合研究提供新思路。

附子理中丸为温中健脾经方，君药附子辛热燥烈，毒效双重，然而全方以全粉制丸，制剂却不显毒燥之性。本课题基于中药丸剂“丸者缓也”实现减毒存效的中药制剂理论精髓，探索了中药丸剂附子理中丸以剂型因素赋予该制剂“去性存用”的特性。.在物质基础方面，课题组首先开展了体外溶出度研究，发现附子理中丸中的“毒效成分”生物碱能够缓慢持久释放，且溶出总量减少；其次开展了血清药物化学研究，鉴定了67种体外成分，26种入血成分，并发现附子生物碱在复方中的相对吸收含量明显低于其单用；最后课题组开展了附子理中丸剂与汤剂剂型的成分吸收“量-时”关系差异研究，发现丸剂剂型与汤剂剂型的成分吸收特征存在显著性差异，在15min，汤剂剂型有47个优势吸收入血成分，丸剂剂型有19个优势吸收入血成分。在30min，汤剂剂型有47个优势吸收入血成分，丸剂剂型有106个优势吸收入血成分，丸剂剂型比汤剂剂型更晚取得吸收优势。综上研究，课题组发现附子理中丸的“丸者缓也”剂型特征在物质基础的溶出和吸收方面可初步体现，该剂型特征通过减缓“毒效成分”生物碱的溶出释放，可实现“去附子理中丸毒燥之性”的作用。.在药效应答方面，课题组主要开展了附子理中丸温中健脾功效的药效学研究，通过脾虚模型建立、网络药理学、代谢组学、元基因组学、因子分析等系列实验研究，发现了附子理中丸治疗脾阳虚型疾病的82个靶点，21条信号通路，10条主要代谢通路和18个关键菌群，初步揭示了附子理中丸的药效应答机制，及附子理中丸剂与汤剂的药效应答差异。综上所述，课题组发现附子理中丸具有抗炎、抗氧化、调节胃肠动力、调节机体免疫、修复肠黏膜损伤、调节机体能量代谢等药理作用，是其“存温中之用”的具体表现。.本课题从物质基础和药效应答方面科学地阐释了“丸者缓也”剂型特征赋予附子理中丸“去性存用”的作用特性，并探索了传统中药制剂理论与现代研究方法相结合的中药经典剂型研究新思路，为丸剂临床合理应用提供了科学依据。