生草乌及配伍诃子的整合TK-TD模型研究

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...

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

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.