灯盏花素对普伐他汀大鼠体内转运过程影响的机制研究

Mechanism of Influence of Breviscapine on the Transport Process of Pravastatin in Rats

目的:探究灯盏花素对大鼠体内普伐他汀转运过程影响的作用机制,为临床合理用药提供数据支撑。方法:正常SD大鼠24只,随机分为生理盐水组、普伐他汀组、灯盏花素组和普伐他汀+灯盏花素组,每组6只。正常KM小鼠60只,随机分为普伐他汀组和普伐他汀+灯盏花素组,每组30只。按照不同剂量给药后采集大鼠胆汁样品和小鼠组织样品处理,采用高效液相色谱法测定样品中普伐他汀的药物浓度;采用RT-PCR和WB技术检测单独及联合给药对大鼠肝脏中Mrp2转运体基因表达和蛋白表达水平的影响。结果:与普伐他汀组比较,普伐他汀+灯盏花素组中除脑组织以外各组织内普伐他汀的药物浓度显著增加(P<0.05);普伐他汀的胆汁分泌量明显降低(P<0.01);与生理盐水组比较,普伐他汀组Mrp2基因和蛋白表达均无明显变化(P>0.05),灯盏花素组及普伐他汀+灯盏花素组中Mrp2转运体基因表达量明显下降(P<0.05),蛋白含量略有减少,但差异无统计学意义(P>0.05)。结论:联用后,灯盏花素可能通过竞争抑制Mrp2转运体功能,使普伐他汀外排转运减慢,体内药物浓度增加,进而提高普伐他汀的临床疗效。

Objective:To reveal the mechanism of the effect of breviscapine on the transport process of pravastatin in rats,and to provide a scientific basis for the rational use of breviscapine and pravastatin in clinical practice.Methods:24 normal SD rats were randomly divided into normal saline group,pravastatin group,breviscapine group,and pravastatin+breviscapine group,with 6 rats in each group.60 normal KM mice were randomly divided into pravastatin group and pravastatin+breviscapine group,with 30 mice in each group.Rat bile samples and mouse tissue samples were collected for treatment after different doses of the drugs were administered.High-performance liquid chromatography(HPLC)was employed to measure the drug concentration of pravastatin in the samples.RT-PCR and Western Blot techniques were used to determine the effects of individual and combined drugs on the gene and protein expression levels of Mrp2 transporter in rat liver.Results:Compared with the pravastatin group,the drug concentration of pravastatin in all tissues except brain tissue significantly increased in the pravastatin+breviscapine group(P<0.05);and the bile secretion of pravastatin significantly decreased(P<0.05).Compared with the normal saline group,the gene and protein expression of Mrp2 in the pravastatin group did not change significantly(P>0.05).The expression of Mrp2 transporter gene in the breviscapine group and the breviscapine+pravastatin group decreased(P<0.05),and the protein content was slightly reduced,but there was no statistical difference between the two groups(P>0.05).Conclusion:Through combination,breviscapine may inhibit the function of transporter Mrp2 through competition,slow down the efflux of pravastatin and increase the drug concentration in the body,thereby improving the clinical efficacy of pravastatin.