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目的:研究普鲁卡因胺经羧酸酯酶1(CES1)影响咪达普利代谢的作用。方法:进行体外大鼠肝微粒体酶孵育实验,通过测定CES1特异性底物咪达普利的代谢产物咪达普利拉的含量,来研究普鲁卡因胺对CES1活性的影响;将12只SD大鼠随机分为两组,分别给予生理盐水和普鲁卡因胺(50mg·kg~(-1)),连续4 d,随后灌胃给予咪达普利(10mg·kg~(-1)),于给药后不同时间点采集血样,采用LC-MS/MS法测定血浆中咪达普利拉的含量,计算药动学参数,来研究普鲁卡因胺对咪达普利在大鼠体内代谢的影响。结果:在体外研究中,普鲁卡因胺对CES1的调节呈现剂量依赖型抑制特征。体内研究发现,普鲁卡因胺显著降低咪达普利拉AUC_(0-24h),AUC_(0-∞)和C_(max)。结论:普鲁卡因胺显著抑制CES1的活性,从而抑制咪达普利拉的形成,对酯类前药代谢的研究有一定的意义。
Objective: To investigate the effect of procainamide on the metabolism of imidapril via carboxylesterase 1 (CES1). Methods: In vitro rat liver microsomal enzyme incubation experiments were conducted to determine the effect of procainamide on the activity of CES1 by measuring the content of imidapril, a metabolite of the specific substrate for imidacloprid of CES1; Only SD rats were randomly divided into two groups and given normal saline and procainamide (50 mg · kg -1) respectively for 4 consecutive days, followed by intragastric administration of Imidapril (10 mg · kg -1) 1)), blood samples were taken at different time points after administration, the content of imidapril in plasma was determined by LC-MS / MS, and the pharmacokinetic parameters were calculated to study the effects of procainamide on imidapril The effect of metabolism in rats. RESULTS: In vitro studies demonstrated that procainamide regulates CES1 in a dose-dependent manner. In vivo studies showed that procainamide significantly reduced imidaprilla AUC_ (0-24h), AUC_ (0-∞), and Cmax. Conclusion: procainamide significantly inhibits the activity of CES1 and thus inhibits the formation of imidapril and has some significance for the study of the metabolism of ester prodrugs.