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

“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。

“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.