摘要
目的评估不同肾损伤模型对大鼠白消安药代动力学和尿排泄清除率的影响,并探讨血/尿动力学关系。方法分别建立阿霉素肾病(ARN)和马兜铃酸肾病(AAN)模型,研究肾病大鼠静脉注射白消安1 mg·kg^(-1)后的药代动力学和肾排泄清除率变化。以一房室模型对血/尿数据拟合,以肾排泄清除率桥接血/尿动力学曲线。结果肾损伤未导致白消安尿排泄率显著变化,但ARN大鼠中白消安的AUC_(0~t)显著升高(P<0.05),总清除率显著降低(P<0.05),而在AAN大鼠中药代动力学参数未发生显著变化。与总体法计算的CL_(r,T)相比,单点法计算的CL_(r,t)变异较大,且存在前低后高的时间依赖性。结论本研究结果显示白消安的肾排泄清除率没有受到肾损伤的影响。尿液替代血浆的药代动力学研究策略的关键指标--单点法的CL_(r,t)表现出较大变异,原因为尿排泄曲线拟合所获得的斜率和截距参数被低估,因此,该策略还需进行深入优化并对拟合结果进行综合验证。
Objective To evaluate the effect of different renal injury models on the pharmacokinetics and renal clearance(CL_(r)) of busulfan in rats,and to determine the relationship between blood and urodynamics.Methods Adriamycin nephropathy(ARN)and aristolochic acid nephropathy(AAN)models were established respectively to determine the pharmacokinetics and CL_(r) of rats after intravenous injection of busulfan(1 mg·kg^(-1)).The plasma/urine data were fitted by one-compartment model,and the renal clearance was used to bridge the plasma/urine dynamic curve.Results Nephropathy did not cause obvious changes in the urinary excretion rate of busulfan.In ARN rats,AUC_(0~t) of busulfan increased significantly(P<0.05)and the CL decreased significantly(P<0.05),but its pharmacokinetics did not change much in AAN rats.Compared with the CL_(r,T) calculated by totality method,the CL_(r,t) calculated by the single-point method had a greater variation,with a time dependence from low to high.Conclusion The CL_(r) of busulfan is not affected by nephropathy.As the key index of pharmacokinetics research strategy of plasma replaced urine,CL_(r,t) of single point method showed great variation because that the slope and intercept parameters obtained by urine excretion curve fitting are underestimated.This strategy needs further optimization and the fitting results should be comprehensively verified.
作者
李广路
王福润
朱芳媚
沃茹烨
庄笑梅
张文鹏
张天宏
王全军
LI Guang-lu;WANG Fu-run;ZHU Fang-mei;WO Ru-ye;ZHUANG Xiao-mei;ZHANG Wenpeng;ZHANG Tian-hong;WANG Quan-jun(State Key Laboratory of Medical Countermeasures and Toxicology,Institute of Pharmacology and Toxicology,National Beijing Center for Drug Safety Evaluation and Research,Academy of Military Sciences,Beijing 100850)
出处
《中南药学》
CAS
2022年第11期2506-2513,共8页
Central South Pharmacy
基金
国家“重大新药创制”科技重大专项资助项目(No.2018ZX09721003-001-005)。
作者简介
李广路,男,硕士研究生,主要从事毒物药物分析研究,email:LiguangluJSYX@163.com;通信作者:张文鹏,男,助理研究员,主要从事药代动力学研究,email:wpzhang@bmi.ac.cn;通信作者:张天宏,男,副研究员,主要从事药代动力学研究,email:wdzth@sina.com;通信作者:王全军,男,研究员,博士研究生导师,主要从事药物毒理学与药物临床前安全评价,email:wangquanjunbeijing@163.com。
