咪达普利在免疫性肝损伤大鼠体内的药动学特征

目的:探讨咪达普利在免疫性肝损伤大鼠体内的药动学特征。方法:采用腹腔注射卡介苗(BCG)和脂多糖(LPS)建立大鼠免疫性肝损伤模型。模型组和正常对照组分别灌胃给予咪达普利(10 mg·kg-1),于给药后不同时间点采血,采用LC-MS/MS法测定血浆中咪达普利代谢产物咪达普利拉的浓度,计算药动学参数。结果:与正常大鼠相比,免疫性肝损伤大鼠体内咪达普利拉的的AUC0-12h、AUC0-∞和Cmax显著降低(P<0.05)。结论:免疫性肝损伤状态下,咪达普利的水解代谢受到显著抑制,药动学发生明显改变,该作用可能与LPS抑制羧酸酯酶1(CES1)的活性相关。

Pharmacokinetics of imidapril in rats with immunological liver injury

OBJECTIVE To investigate the pharmacokinetics of imidapril in SD rats with immunological liver injury.METHODS The animal model of immunological liver injury was established by intraperitoneal injection of lipopolysaccharide(LPS) plus Bacille-Calmette-Guerin(BCG) in rats.Rats were randomly divided into two groups:normal control group and immunological liver injury model group.The two groups were administrated with imidapril (10 mg·kg-1) by intragastric administration and plasma concentration of imidaprilat was determined by LC-MS/MS.Based on the data,the pharmacokinetic parameters were calculated.RESULTS Compared with the normal control group,the AUC0-12h,AUC0-∞ and Cmax of imidaprilat were decreased significantly(P<0.05) in immunological liver injury model group.CONCLUSION In the state of immunological liver injury,the hydrolysis of imidapril was inhibited significantly.The underlying mechanism may be related to the down regulation of the expression of carboxylesterase 1 by LPS.