黄连碱对内毒素发热大鼠解热作用的PK-PD研究  

Pharmacokinetic-pharmacodynamic study on antipyretic effects of coptisine on endotoxin-induced pyrexia of rats

作　　者：王丽[1] 胡樱凡 童东 左芳[1] 魏志成[1] 孟宪丽[1] 王平[1] 

机构地区：[1]成都中医药大学药学院,四川成都611137

出　　处：《中国药理学通报》2017年第4期552-556,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81274111)

摘　　要：目的建立药动学(PK)-药效学(PD)结合模型来评价黄连碱解热作用的相关特点。方法以100μg·kg^(-1)内毒素复制大鼠炎性热症模型,给药组大鼠尾静脉注射黄连碱高剂量(3.87 mg·kg^(-1))或低剂量(1.93 mg·kg^(-1))后,于不同时间点测量大鼠肛温,并采集血浆样本后UPLC法测定血药浓度。采用Monolix软件以无协变量的群体计算法对黄连碱血药浓度与解热效应进行PK-PD模型建模、拟合与评价。结果黄连碱能够明显抑制内毒素发热大鼠的体温升高,最终PK模型采用二房室线性消除模型、PD模型采用高斯函数作为体温改变的输入函数,选择E_(max)模型联结PK与PD部分。最终模型拟合较优,模型拟合所得黄连碱解热作用EC50为89.7μg·L^(-1)、E_(max)为1.88℃。结论黄连碱对内毒素发热大鼠解热作用强,效价高,体内分布小,消除快。Aim To establish the pharmacokineticpharmacodynamic（ PK-PD） modeling to characterize the antipyretic effects of coptisine,an active component in coptis chinensis on rats.Methods Nine healthy male Sprague-Dawley（ SD） rats were randomly divided into three groups,each with three.The rats in the first group were injected intravenously with lipopolysaccharide（ LPS,100 μg·kg-1） alone.The second and third group rats were given coptisine high-dose（ 3.87 mg·kg-1） and coptisine low-dose（ 1.93 mg·kg-1） by tail vein injection at 30 min after LPS injection,respectively.Body temperature was measured at different time points,and blood samples from tail vein were collected simultaneously.The blood concentration of coptisine was determined by ultra performance liquid chromatography.Monolix software was used to model PK-PD of coptisine mean plasma concentration and temperature effects,by population computation with non-covariates.Besides.the model with advantage was selected by the fitting goodness.Results Coptisine could inhibit body temperature of endotoxin-induced fever in rats significantly.Two-compartment linear elimination model was used to describe the final PK model.Gaussian function,an input function of body temperature changes,which was used to depict PD model,the PK and PD models were connected by the Emax model.At last,the final model was fitted better;the fitting results indicated that the EC50 of antipyretic effect of coptisine was 89.7 μg · L-1,and the Emax was1.88℃.Conclusions Coptisine has a powerful antipyretic effect on endotoxin-induced pyrexia of rats with high potency,Low in vivo distribution and quick clearance.

关 键 词：黄连碱 内毒素 解热 药动学-药效学 静脉注射 体温 

分 类 号：R-332[医药卫生] R284.1