川芎嗪-丹参配伍前后对药动学及CYP450酶的影响及其相关性

Effects and correlation of ligustrazine hydrochloride-Salviae Miltiorrhizae Radix et Rhizoma compatibility on pharmacokinetics and CYP450 enzyme

探究盐酸川芎嗪与丹参配伍前后对急性心肌缺血(acute myocardial ischemia,AMI)大鼠体内药动学的影响,从代谢酶的角度揭示其配伍前后药动学参数变化的机制。AMI模型大鼠分别单次尾静脉注射丹参注射液(DGI)、川芎嗪注射液(CGI)和参芎葡萄糖注射液(SGI)(丹参素3.78 mg·kg^(-1),迷迭香酸0.049 mg·kg^(-1),川芎嗪13.68 mg·kg^(-1)),于不同时间点眼眶静脉丛采血,并于末次取血点后处死大鼠取出肝脏,采用UPLC-MS/MS检测血浆中丹参素、迷迭香酸、川芎嗪的血药浓度;采用Western blot技术,考察各组大鼠肝脏中CYP1A2、CYP2C11、CYP2C19、CYP2D4、CYP2E1、CYP3A2蛋白表达的情况。药动学结果显示,与CGI组相比,SGI组中的川芎嗪在AMI大鼠体内的T_(1/2)有降低趋势,AUC显著降低(P<0.05);与DGI组相比,SGI组中丹参素和迷迭香酸药动学参数均无显著性差异。蛋白表达结果显示,SGI组中CYP1A2、CYP2C11、CYP2D4、CYP2E1、CYP3A2的表达量较CGI组均显著增加(P<0.05),CYP2C19的表达量较CGI组显著降低(P<0.05)。CYP1A2、CYP2C11、CYP3A2是参与川芎嗪Ⅰ相代谢的同工酶,当丹参与盐酸川芎嗪合用后,这3种酶表达升高,使大鼠体内药动学过程发生变化,川芎嗪的代谢加快。

The present study investigated the effects of ligustrazine hydrochloride(LH)-Salviae Miltiorrhizae Radix et Rhizoma(SM)before and after compatibility on the pharmacokinetics of acute myocardial ischemia(AMI)rats and revealed the mechanism of pharmacokinetic changes from the perspective of metabolic enzymes.AMI rats underwent single injection of SM Glucose Injection,LH Glucose Injection,and LH-SM Glucose Injection in the caudal vein,respectively(3.78 mg·kg^(-1)salvianic acid,0.049 mg·kg^(-1)rosmarinic acid,and 13.68 mg·kg^(-1)ligustrazine).Blood samples were collected from the orbital venous plexus at different time points,and the liver of the rats was removed after the last blood sampling.The plasma concentrations of salvianic acid,rosmarinic acid,and ligustrazine were detected by UPLC-MS/MS.Western blot was used to detect the protein expression of CYP1A2,CYP2C11,CYP2C19,CYP2D4,CYP2E1,and CYP3A2 in the liver of rats in each group.As revealed by the pharmacokinetic results,compared with the LH Glucose Injection group,the LH-SM Glucose Injection group showed a downward trend of T_(1/2)of ligustrazine in AMI rats and decreased AUC(P<0.05).Compared with the SM Glucose Injection,there were no significant differences in the pharmacokinetic parameters of salvianic acid and rosmarinic acid in the LH-SM Glucose Injection group.Protein expression results showed that the expression levels of CYP1A2,CYP2C11,CYP2D4,CYP2E1,and CYP3A2 in the LH-SM Glucose Injection group increased(P<0.05)and the expression level of CYP2C19 decreased(P<0.05)compared with those in the LH Glucose Injection group.CYP1A2,CYP2C11,and CYP3A2 are isoenzymes involved in ligustrazineⅠmetabolism.When LH and SM were used in combination,the expression of these three enzymes increased,which changed the pharmacokinetic process in rats and accelerated the metabolism of ligustrazine.