生草乌所致心脏毒性的毒代动力学/毒效动力学模型研究  

Study on Toxicokinetics/Toxicodynamic Model of Cardiotoxicity Induced by Mongolian Radix Aconiti Kusnezoffii

作　　者：王胜男 苗鑫 董志强 王勇[3] 赵璐璐 谷超 高原 李刚 Wang Shengnan;Miao Xin;Dong Zhiqiang;Wang Yong;Zhao Lulu;Gu Chao;Gao Yuan;Li Gang(Inner Mongolia Medical University,Hohhot 010110;First Affiliated Hospital of Baotou Medical College,Inner Mongolia University of Science and Technology,Baotou 014000;Department of rheumatology,the Affiliated Hospital of Inner Mongolia Medical University,Hohhot 010110)

机构地区：[1]内蒙古医科大学药学院,呼和浩特010100 [2]内蒙古科技大学包头医学院第一附属医院,包头014000 [3]内蒙古医科大学附属医院风湿科,呼和浩特010100

出　　处：《中药药理与临床》2020年第3期122-130,共9页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家自然科学基金(No.81560685)。

摘　　要：目的:本文主要是探讨生草乌所致心脏毒性的毒代动力学/毒效动力学(TK-TD)的研究。创新性的应用了ADAPT 5建立了一个拥有间接响应毒效的整合TK-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合并QT间期的变化。方法:生草乌灌胃给药后大鼠体内的TK-TD模型研究:①血浆药物浓度的测定:雄性SD大鼠随机分为空白对照组和生草乌0.36 g/kg、0.42 g/kg、0.49 g/kg组,单次灌胃给药后0.5、1、1.5、2、3、5、7、10、12和24 h颈动脉取血,记录心率(HR)和QT间期指标,采用UPLC/Q Exactive MS技术测定血浆药物浓度(观测值)。②毒物代谢动力学模型建立:时间t与观测值做药时曲线关系,对4种备选TK模型进行ADAPT 5程序下的最大似然法(ML)测试分析,采用AIC和BIC较小原则选择最优拟合方法和模型,Maltab 2011b收敛和扩展数据后输出模型。③毒物效应动力学模型建立:时间t分别与HR和QT建立时效关系曲线,针对三种生物碱到达Emax的时间(t≈1.5 h^2 h)明显滞后于Cmax(t≈1 h),建立生草乌大鼠血药浓度依赖性的间接毒物效应响应模型,血药浓度-时间-毒效三者的变化速率由Hill’s方程联系。④TK-TD整合模型建立。结果:TK模型为一房室线性一级消除动力学模型,0.49 g/kg生草乌QT间期存在一定剂量-时间依赖性,故对心率和生草乌0.36 g/kg QT间期建立间接毒物效应响应模型的生理相(Biophase)TD模型,对生草乌0.49 g/kg QT间期采用间接毒物效应响应模型的Jusko’s间接响应(IDR)PD模型,输出TK-TD参数。结论:具有房室线性一级消除动力学和间接响应的整合TK-TD模型更适用于解释生草乌口服给药暴露与心脏毒性之间的关系,科学准确地预测生草乌对大鼠的心脏毒性。Objective:To study the toxicokinetics/toxicokinetics(TK-TD)of cardiotoxicity induced by Radix Aconiti Kusnezoffii.An integrated TK-TD model with indirect response to toxicity was established by ADAPT 5 program,as a new quantitative framework to assess the abnormal heart rate and QT interval changes caused by Radix Aconiti kusnezoffii(RAK).Methods:TK-TD model was investigated in vivo after intragastric administration:①Determine of plasma drug concentration:Male SD rats were randomly divided into the control group and Mongolian Radix Aconiti Kusnezoffii groups(0.36 g/kg、0.42 g/kg、0.49 g/kg).After single oral administration,blood was taken from the carotid arteries at 0.5,1,1.5,2,3,5,7,10,12 and 24 h.Heart rate(HR)and QT interval indicators were recorded.Plasma drug concentrations(observations)were determined using UPLC/Q Exactive MS technology.②Toxic kinetic model was established:the relationship between time t and the observation value was plotted,and four alternative TK models were tested by maximum likelihood method(ML)under ADAPT 5 program.AIC and BIC were used to select the best fitting method and model,then the data was converged and expanded by the Maltab 2011 b program.③The toxic effect kinetic model was established:Time t curve with HR and QT was established respectively.The time to reach Emax of three alkaloids(t≈1.5~2 h)was significantly delayed from Cmax(t≈1 h),and the indirect toxic effect response model of blood concentration-dependent was established.The changing rate among blood concentration,time and toxicity was linked by the Hill’s equation.④TK-TD integration model was established:Results:The TK model was an atrioventricular linear first-order elimination kinetic model.There is a dose-time dependence relationship in QT interval of 0.49 g/kg Radix Aconiti Kusnezoffii.Physiological phase(Biophase)TD model of the indirect toxic effect response model was established for the heart rate and QT interval of 0.36 g/kg Radix Aconiti Kusnezoffii.The Jusko’s indirect response(IDR)PD model

关 键 词：生草乌 心率 QT间期 TK-TD模型 心脏毒性 

分 类 号：R285.5[医药卫生—中药学]