The pharmacokinetic interactions of rivaroxaban and repaglinide in rats

JIANG Da-peng; DONG Wei-chong; HE Wen-juan; GONG Ying; ZHANG Zhi-qing; WANG Shu-mei

Abstract：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.