复方丹参胶囊对替格瑞洛在大鼠体内药动学的影响及其机制  

Effect and Mechanism of Compound Danshen Capsules on the Pharmacokinetics of Ticagrelor in Rats

作　　者：周帅[1] 韩战营[1] 迟骁玮 ZHOU Shuai;HAN Zhanying;CHI Xiaowei(Department of Cardiovascular,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Development Center for Medical Science&Technology,National Health Commission of the People's Republic of China,Beijing 100044,China)

机构地区：[1]郑州大学第一附属医院心内科,河南450052 [2]国家卫生健康委员会医药卫生科技发展研究中心,北京100044

出　　处：《医药导报》2021年第12期1652-1658,共7页Herald of Medicine

摘　　要：目的研究复方丹参胶囊对替格瑞洛在大鼠体内药动学的影响,并探讨其作用机制。方法采用平行对照法将16只SD大鼠随机分为对照组和复方丹参胶囊组(90 mg·kg^(-1)),连续7 d分别每天灌胃给予0.9%氯化钠溶液和复方丹参胶囊。第8天,两组大鼠均在常规给药30 min后灌胃给予替格瑞洛(20 mg·kg^(-1)),并于给药前和给药后0.08,0.25,0.5,1,1.5,2,3,4,6,8,10,24及36 h于大鼠眼内眦采血,采用液相色谱-质谱串联(LC-MS/MS)法测定大鼠血浆中替格瑞洛的浓度,并采用WinNonlin计算药动学参数;采用实时荧光定量-聚合酶链反应(qRT-PCR)检测两组大鼠给药后肝组织中CYP3A1及CYP3A2 mRNA表达;采用Western blotting检测两组大鼠给药后肝组织中CYP3A2蛋白表达;采用肝微粒体孵育体系检测CYP3A酶活性。结果连续7 d灌胃给予复方丹参胶囊可使大鼠体内替格瑞洛的C_(max)、AUC_(0-t)及AUC_(0-∞)显著降低32.03%,30.65%及38.89%(P<0.01),且使替格瑞洛的CL/F、V_(z)/F显著升高至1.43及1.37倍(P<0.01);连续7 d灌胃给予复方丹参胶囊可显著诱导大鼠肝脏中CYP3A2 mRNA及蛋白表达;复方丹参胶囊可显著升高大鼠CYP3A酶活性。结论连续灌胃给予大鼠复方丹参胶囊可显著降低其体内替格瑞洛的暴露量,提高其清除率及表观分布容积,其作用机制可能与诱导CYP3A2活性及蛋白表达有关。Objective To investigate the effect of compound Danshen capsules on pharmacokinetics of ticagrelor in rats and the mechanism mediated.Methods Sixteen male Sprague-Dawley rats were randomly divided into the control and Danshen capsules group.Pharmacokinetic parameters of ticagrelor were determined in male rats after the administration of ticagrelor(20 mg·kg^(-1),i.g.)to rats in the presence and absence of the co-adminsitration of Danshen capsules(90 mg·kg^(-1),i.g.)for 7 days.Then their liver tissue was isolated and analyzed for mRNA expressions of CYP3A1 and CYP3A2.CYP3A2 protein expression was analyzed by Western blotting.The activity of CYP3A were detected in LC-MS/MS.Results Compound Danshen capsules(90 mg·kg^(-1),i.g.,7 days)significantly decreased the C_(max),AUC_(0–t),and AUC_(0–∞)of orally administered ticagrelor by 32.03%,30.65%and 38.89%folds,respectively(P<0.01)and increased the CL/F and V_(z)/F by 1.42 and 1.37 folds,respectively(P<0.01).Further study revealed that the expression of CYP3A2 was significantly increased in Danshen capsules treated liver with oral multiple doses.The mRNA and protein expression of CYP3A2 were increased Danshen capsules treated groups with multiple doses.And the activities of CYP3A were largely increased.Conclusion Compound Danshen capsules decreased the oral bioavailability of ticagrelor significantly in rats,which may be mainly attributable to the induction of CYP3A2 protein expression and activity.Administration of Danshen capsules plus ticagrelor may require dose adjustment and closely monitoring of ticagrelor plasma concentrations.

关 键 词：复方丹参胶囊 替格瑞洛 药动学 细胞色素P4503A1 细胞色素P4503A2 

分 类 号：R972[医药卫生—药品]