一种基于靶器官效应和分布的中药毒效成分评价方法及其在补骨脂毒性物质基础研究中的应用

The safety of traditional Chinese medicine (TCM) has attracted many interests from researchers. But since the composition of traditional Chinese medicine is very complex, screening and identifying toxic ingredients from TCM is usually difficult. The techniques of high throughput screen in vitro and the method of extracting and isolating monomer composition from traditional chinese medicine then tested in vivo are both far from impeccable..The project was base on “serum pharmacology and serum pharmacochemistry and target organ toxicology”. Drug concentration in target organ often differs from that in blood. Therefore, we propose a screening method according to the effects and distribution of drugs in the target organ. It uses drug kinetic parameters of target organ to correct experimental results in vitro. And the safety index (S=T/E), which is similar to the therapeutic index, was used to evaluate the relative safety of various ingredients. The aim of this project is to establish a simple feasible and accurate method of screening toxic ingredients in TCM and provide a new idea about safety and toxic substances of TCM. With effects and distribution of the components in Fructus Psoraleae, at least 20 components from Fructus Psoraleae Psoralea corylifolia will be evaluated of their toxicity and efficacy using this new method. And at least 6 components will be evaluated in vivo. Identifying toxic components in Fructus Psoraleae would support studies to reducetoxicity of Fructus Psoraleae and guide improvement of Chinese medicine formula containing Fructus Psoraleae.

中药安全性问题受到广泛重视，然而由于中药成分复杂，使寻找中药毒性成分是一个普遍的难题。传统的分离各成分、然后进行整体动物实验评价的方法，以及体外细胞实验高通量筛选的方法都有其固有的缺点。.本项目在“血清药理学，中药血清药物化学和靶器官毒理学”的基础上，根据靶器官药物浓度变化趋势常与血液中并不相同的现象，提出“基于靶器官效应和分布的毒效筛选方法”，使用靶器官药物动力学参数对体外实验结果进行校正，并引入类似于药物“治疗指数”的指标，用安全指数S=T/E评价中药成分的相对安全性。旨在建立一种简单、可行、准确的中药毒性成分筛选方法，为中药安全性和毒性物质基础研究提供新思路。结合补骨脂中各成分对靶器官效应（毒-效）和分布情况，使用新本方法对补骨脂中至少20个成分进行毒效评价，选择最少6个成分进行体内实验评价来验证方法的可行性，阐明补骨脂的毒效物质基础，为补骨脂减毒和含补骨脂的中成药二次开发提供支持。

本项目提出使用靶器官药物动力学参数对体外实验结果进行校正，并引入类似于药物“治疗指数”的指标，用安全指数S=T/E评价中药成分的相对安全性。旨在建立一种简单、可行、准确的中药毒性成分筛选方法，为中药安全性和毒性物质基础研究提供新思路，并将其应用于补骨脂的毒性成分研究。完成了10个产地29个批次的补骨脂药材的UHPLC指纹图谱研究。对建立了补骨脂中多种成分的LC-MS/MS检测方法，在补骨脂药材中检测到19个成分，在口服给予补骨脂后大小鼠体内检测到14个成分，测定了这些成分的血药浓度和肝脏等靶器官分布情况。对相应成分进行了体外肝毒性和成骨、破骨细胞作用的评价获得了最小毒性剂量、IC50、有效剂量等数据。并对补骨脂素、异补骨脂素、补骨脂酚、补骨脂甲素、补骨脂乙素和补骨脂定进行了体内抗骨质疏松和毒性评价研究。比较了6个成分体内外安全性评价结果，都表明异补骨脂素安全性最差，证明项目提出的方法一致性较好、可以用来进行评价。最后，根据本项目提出的“基于靶器官效应和分布的毒效成分筛选方法”，对补骨脂中主要成分进行了评价，结果表明，补骨脂素、异补骨脂素和补骨脂酚是补骨脂肝毒性的三个关键成分。为补骨脂的减毒和含补骨脂的中成药二次开发、安全使用提供了实验研究数据支持。