生草乌及配伍诃子的整合TK-TD模型研究  

Study on integrated TK-TD model of Radix Aconiti Kusnezoffii and Fructus Chebulae

作　　者：赵璐璐 苗鑫[1] 王胜男 高原[1] 谷超 李刚 ZHAO Lu-lu;MIAO Xin;WANG Sheng-nan;GAO Yuan;GU Chao;LI Gang(Inner Mongolia Medical University,Hohhot 01O110.China)

机构地区：[1]内蒙古医科大学,呼和浩特010110 [2]内蒙古医科大学药学院,呼和浩特010110

出　　处：《中华中医药杂志》2021年第2期1012-1019,共8页China Journal of Traditional Chinese Medicine and Pharmacy

基　　金：国家自然科学基金项目(No.81560685)。

摘　　要：目的:应用整合的毒物代谢动力学(TK)-毒物效应动力学(TD)模型作为一种新的定量框架来评估生草乌引起的异常心率(HR)合并QT间期变化。初步应用于探讨草乌诃子1∶1、1∶3、3∶1配伍后的TK-TD拟合,进一步研究诃子草乌配伍"减毒存效"可能的机制。方法:建立TK-TD结构模型和原假设H0:Σ=S,采用Amos 24.0进行相关性分析和模型检验,运用建立的TK-TD模型框架对草乌与诃子1∶1、1∶3、3∶1配伍结果进行模拟,ADAPT 5用于模拟TK-TD模型。结果:采用最大似然法(ML)法,0.5~12h拟合值全部落到最大和最小区域范围内。通过AMOS分析对假设模型的正确性验证得到变量的载荷系数均>0.7,χ2值为4.169,显著性水平PL=0.041表示有显著性差异;RMSEA值<0.08模型拟合最好,得到0.162与0.08较为接近,说明模型拟合好。同时,HR和QT间期的载荷系数(相关系数)为-0.965,说明二者间呈现负相关性;草乌与诃子按照1∶1、1∶3、3∶1比例配伍后的TK-TD整合模型拟合结果显示模型整体对配伍后次乌头碱的大鼠体内过程和效应的拟合度较低。结论:采用草乌建立的TK-TD模型虽不能很好地预测草乌与诃子配伍后的TK和TD过程,但整合的TK-TD模型能够科学准确地预测大鼠生草乌中毒的心脏毒性。Objective:The integrated TK-TD model was established using ADAPT 5 as a new quantitative framework to evaluate abnormal heart rate and QT interval changes caused by Radix Aconiti Kusnezoffii(RAK).Furthermore,the established TK-TD model was applied to the fitting of the 1∶1,1∶3 and 3∶1 compatibility of Mongolian medicine Fructus Chebulae to explore the possible mechanism.Methods:Establish TK-TD structural model and hypothesis H0:Σ=S,using Amos 24.0 for correlation analysis and model checking,using the established TK-TD model framework to Radix Aconiti Kusnezoffii and Fructus Chebulae(1∶1,1∶3 and 3∶1)compatibility to simulate the results,ADAPT 5 was used to simulate the TK-TD model.Results:Using the maximum likelihood method(ML),it could be seen that the 0.5~12 hour fitting values all fall within the maximum and minimum regions.The correctness of the hypothesis model was verified by AMOS analysis.The load factor of the variable was greater than 0.7,theχ2 value was 4.169,and the significance level=0.041 indicated significant difference.The RMSEA value<0.08 was the best fit.A closer comparison between 0.162 and 0.08 indicates that the model fits well.At the same time,the load factor(correlation coefficient)between HR and QT interval was-0.965,indicating a negative correlation between heart rate and QT.The fitting of TK-TD after compatibility with Fructus Chebulae in 1∶1,1∶3 and 3∶1 ratio showed that the fitting degree of TK model was better than TD,but the overall fit of the model to the in vivo process and effect was lower.Conclusion:Although the TK-TD model established by Radix Aconiti Kusnezoffii can not well predict the TK and TD process after compatibility of Radix Aconiti Kusnezoffii and Fructus Chebulae,the integrated TK-TD model can scientifically and accurately predict the cardiotoxicity of raw Radix Aconiti Kusnezoffii poisoning in rats.

关 键 词：整合TK-TD模型 生草乌 诃子 配伍 心率 QT间期 

分 类 号：R285.5[医药卫生—中药学]