利伐沙班和瑞格列奈在大鼠体内药动学相互作用

摘要

目的:建立高效液相色谱-串联质谱(HPLC-MS/MS)法,同时测定大鼠血浆中利伐沙班和瑞格列奈浓度,并初步考察两药的药动学相互作用.方法:将54只雄性wistar大鼠随机分为单用利伐沙班组、单用瑞格列奈组和联合用药组,每组18只,于给药前后不同时间点眼内眦采集血样,采用HPLC-MS/MS法同时测定两药的血药浓度.色谱柱为Diamonsil C18柱,流动相为乙腈-0.1％甲酸水溶液(60:40),质谱条件为电喷雾离子源(ESI源),正离子模式检测,扫描方式为多反应监测(MRM),用于定量分析的离子反应分别为m/z 436.0→m/z144.9(利伐沙班)、m/z 452.9→m/z 162.3(瑞格列奈)和m/z 324.1→m/z127.2(格列齐特).利伐沙班、瑞格列奈检测质量浓度线性范围分别为12.5 ～800 ng·mL-1 (r =0.997 1)和2.5～160ng·mL-1(r =9 995).结果:与单用瑞格列奈组相比,联合用药组瑞格列奈各项参数没有显著变化;与单用利伐沙班组相比,联合用药组利伐沙班AUC0-24,AUC0-∞和Cmax明显增大(P＜0.05),清除率(CL)明显减小(P＜0.05).结论:该方法专属性强、灵敏度高、准确性好,可同时测定瑞格列奈和利伐沙班血药浓度,且两药联用时存在一定的药动学相互作用.%Objective:To establish a method for simultaneous determination of rivaroxaban and repaglinide in rat plasma by HPLC-MS/MS and study their pharmacokinetic interactions.Methods:Fifty-four male Wistar rats were divided into three groups:repaglinide group,rivaroxaban group and co-administration group.Blood samples were collected at different time before and after oral administration.Rivaroxaban and repaglinide in rat plasma were separated by Diamonsil C18 column with the mobile phase consisting of acetonitrile-0.1％ formic acid (60:40).Gliclazide was used as the internal standard.Detection and quantification were performed by using ESI-MS.The detector was operated in selected reaction-monitoring mode at m/z 436.0→m/z 144.9 for rivaroxaban,m/z 452.9 →m/z 162.3 for repaglinide,and m/z 324.1→m/z 127.2 for gliclazide,respectively.The calibration curves were linear over the concentration range of 12.5 ～ 800 ng· mL-1 (r =0.997 1) for rivaroxaban and 2.5 ～ 160 ng· mL-1 (r =0.999 5) for repaglinide,respectively.Results:The C AUC0-t and AUC0-24 of rivaroxaban in the coadministration group increased significantly (P ＜ 0.05) and the CL decreased significantly (P ＜ 0.05) compared with single drug administration group,but there existed no significant differences in the pharmacokinetic parameters of repaglinide after co-administration with rivaroxaban.Conclusion:The method is specific,sensitive and accurate for determining the concentrations of repaglinide and pravastatin in rat plasma.There exist pharmacokinetic interactions between rivaroxaban and repaglinide.