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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 pharmacokinetic model of levodopa (LD) in rats and investigate the influencing factors of LD pharmacokinetic parameters. Methods: Fourteen rats were randomly divided into high and low dose groups, given a single oral administration of dopprous hydrazine tablets. Peripheral blood was collected from rat striatum by dialysis with brain microdialysis. Peripheral blood was collected at the same time. The dialysate and plasma LD concentrations were determined by high performance liquid chromatography-electrochemical method. Nonlinear mixed effect model , NONMEM) for population pharmacokinetic data analysis. Results: Statistical models including fixed effect parameters such as individual variability, individual variability, body weight and dose were established. The estimated values of the raw data were all within 2.5% ~ 97.5% of the estimated Bootstrap values Visual predictive assessment showed that the concentration of LD in peripheral blood and central striatum of rats was basically within the range of 90% percentile. The final model established was stable, effective and had a strong predictive power. Body mass can affect LD pharmacokinetic parameters K32. Conclusion: The established group pharmacokinetic model can better describe the pharmacokinetics of LD in the central and peripheral blood of rats. The dose of rat has no effect on the pharmacokinetic parameters of LD, and the body weight can affect the pharmacokinetic parameters of LD.