微透析法研究左氧氟沙星气管内雾化和静脉注射给药的药动学参数

Study on pharmacokinetic parameters of levofloxacin intratracheal atomization and intravenous administration by microdialysis

目的探究左氧氟沙星气管内雾化和静脉注射给药后的体内药动学差异,为其吸入溶液剂的开发提供参考。方法采用微透析采样联合HPLC法,测定大鼠气管内雾化和静脉注射给药后肺微透析液和血浆的药物质量浓度,计算各给药途径的药动学参数,并对比分析其差异。结果气管内雾化后肺黏液的药时曲线下面积(AUC(0~t)EFL)、最大药物质量浓度(C max)、半衰期(t 1/2 z)、清除率(CLz)和分布系数(AUC(0~t)EFL/AUC(0~t)plasma比值)分别为334.538,536.81,2.231,0.087和36.510;静脉注射给药后相关值分别为23.006,6.92,1.134,1.239和0.390,结果表明差异具有显著统计学意义。结论气管内雾化相对于静脉注射给药,t 1/2 z显著延长,CLz降低,AUC(0~t)EFL/AUC(0~t)plasma比值明显偏高,实现药物在肺黏液部位的高效蓄积效应;同时气管雾化给药后的血浆药物峰质量浓度和总体质量浓度水平均低于静脉给药,意味着无关组织的负荷药量小,无关效应低。

Objective To explore the pharmacokinetic differences of levofloxacin after intratracheal atomization and intravenous administration,so as to provide reference for the development of inhalation solution.Methods Microdialysis sampling combined with HPLC was used to determine the drug concentration in pulmonary microdialysis fluid and plasma of rats after intratracheal atomization and intravenous administration.The pharmacokinetic parameters of each route were calculated and the differences were compared and analyzed.Results The area under drug time curve(AUC(0-t)EFL),maximum drug concentration(C max),half life(t 1/2 z),clearance rate(CLz)and distribution coefficient(AUC(0-t)EFL/AUC(0-t)plasma)of lung mucus after intratracheal atomization were 334.538,536.81,2.231,0.087 and 36.510;the correlation values after intravenous administration were 23.006,6.92,1.134,1.239 and 0.390,respectively.The difference is statistically significant.Conclusion Compared with intravenous administration,the t 1/2 z of intratracheal atomization administration is significantly prolonged and CLz rate decreased,and the ratio of AUC(0-t)EFL/AUC(0-t)plasma is significantly higher,which achieves the high accumulative effect of drugs in lung mucus.Meanwhile,the peak concentration and total concentration of drugs in plasma after tracheal administration are lower,which means the load of drugs in unrelated tissues is small and the irrelevant effect is low.