NONMEM法建立大鼠外周和中枢左旋多巴群体药动学模型  

Peripheral and central population pharmacokinetic model of levodopa in rats by NONMEM

作　　者：韩文迪[1] 王长连[1] 林玮玮[1] 黄品芳[1] 刘亦伟[1] 

机构地区：[1]福建医科大学附属第一医院药学部,福建福州350005

出　　处：《中国医院药学杂志》2015年第24期2178-2182,共5页Chinese Journal of Hospital Pharmacy

基　　金：福建省自然科学基金资助项目(编号:2009J01136)

摘　　要：目的：建立大鼠左旋多巴（levodopa,LD）群体药动学模型,考察LD药动学参数的影响因素。方法：14只大鼠随机分为高、低两个剂量组,单次灌胃给予多巴丝肼片。采用脑微透析技术收集大鼠纹状体细胞外液透析液,同时采集外周血;高效液相色谱-电化学法测定透析液及血浆LD浓度,并利用非线性混合效应模型（Nonlinear mixed effect model,NONMEM）进行群体药动学数据分析。结果：建立了包含大鼠个体间变异、个体自身变异及体质量、给药剂量等固定效应参数的统计学模型,原始数据估算的参数值均位于Bootstrap估算参数值的2.5%~97.5%范围内,视觉预测评估法显示建模大鼠外周血和中枢纹状体LD浓度基本位于90%百分位数范围之内,所建立的最终模型稳定、有效、且有较强的预测能力。体质量可影响LD药动参数K32。结论：建立的群体药动学模型能较好地描述LD在大鼠中枢及外周血的药动学特点。大鼠给药剂量对LD药动参数无影响,体质量可影响LD药动参数。OBJECTIVE To establish a population pharmacokinetic model of levodopa（LD）in rats.METHODS SD rats were randomly divided into two groups：high dose group and low dose group.All rats received LD/benserazide（BZE）by oral administration.Dialysates of striatum were collected by microdialysis and blood samples were drawn simultaneously.Concentrations of LD were determined by（high performance liquid chromatography-electrochemical detection,Pharmacokinetic）HPLC-ECD.Pharmacokinetic parameters of LD were evaluated by applying NONlinear Mixed Effects Model（NONMEM）.RESULTS With application of NONMEM,a statistic model of LD is established,including effect of body weight,dosage,variability between individuals and intraindividual variation.Bootstrap and visual predictive check showed that final model of LD was stable,effective and predictable.Meanwhile,it was found that weight could affect none of LD pharmacokinetic parameters except for K32.CONCLUSION With application of NONMEM,apopulation pharmacokinetic model of LD is established,which is capable of depicting pharmacokinetics of LD in striatal extracelluar fluid and plasma.It is found that body weight can affect LD pharmacokinetic parameters,while dose has no effects on any pharmacokinetic parameter of LD.

关 键 词：纹状体 左旋多巴 群体药动学 非线性混合效应模型 

分 类 号：R969.1[医药卫生—药理学]