Drug-drug Interactions Between Rivaroxaban And Simvastatin In Rats

Objective:To establish a method for determination of rivaroxaban,simvastatin and simvastatin acid in rats plasma by HPLC-MS/MS and then to study their pharmacokinetic interactions.Methods:Sixty male wistar rats were divided into four groups:rivaroxaban group;rivaroxaban combined with simvastatin group;simvastatin group;simvastatin combined with rivaroxaban group,fifteen in each group.Blood samples were collected at different times before and after oral administration.Rivaroxaban and simvastatin in rats plasma were separated by Diamonsil C₁₈ with the mobile phase consisting of acetonitrile-acetate solution（0.1%formic acid to p H 4.5）（75:25,V/V）.Lovastatin and ticagrelor was used as the internal standard.Detection and quantification were performed by using ESI.The detector was operated in selected reaction-monitoring mode at m/z436.0→144.9 for rivaroxaban,m/z 419.5→199.1 for simastatin,m/z435.5→319.1 for simastatin acid,m/z 405.3→199.2 for lovastatin and m/z521.2→361.2 for ticagrelor.Results:The pharmacokinetic parameters of rivaroxaban in the test group and control group were as follows:AUC_0-24 were（2777±989.2）ng·h·m L^-1 and（2599±791.8）ng·h·m L^-1;AUC_0-∞were（3396±1409）ng·h·m L^-1and（3053±1116）ng·h·m L^-1;t_1/2 were（9.25±4.18）h and（8.06±3.52）h;T_maxwere（0.60±0.13）h and（0.65±0.28）h;CL were（0.88±0.34）L·（h·kg）^-1and（0.95±0.32）L·（h·kg）^-1;V were（11.07±4.48）L and（10.37±4.43）L;C_maxwere（507.1±132.4）ng·m L^-1and（424.9±145.3）ng·m L^-1.Compared with the control group,there was no significant difference in pharmacokinetic parameters in the test group（P>0.05）.The pharmacokinetic parameters of simvastatin and simvastatin acid in the test group and control group were as follows:AUC_0-24 were（17.87±18.03）and（11.87±5.99）ng·h·m L^-1,（175.9±86.36）and（108.1±33.91）ng·h·m L^-1;AUC_0-∞were（25.01±29.48）and（14.46±6.80）ng·h·m L^-1,（188.5±31.10）and（116.3±32.28）ng·h·m L^-1;CL were（1.21±0.70）and（1.73±0.68）L·h^-1·kg^-1,（0.12±0.05）and（0.18±0.06）L·h^-1·kg^-1;t_1/2 were（5.84±4.41）and（5.49±4.76）h,（5.30±2.86）and（6.84±5.22）h;T_maxwere（0.78±0.13）and（0.78±0.25）h,（0.85±0.21）and（0.76±0.14）h;V were（12.79±5.32）and（10.96±7.04）L·kg^-1,（1.92±0.50）and（1.76±1.26）L;C_maxwere（4.44±1.37）and（4.23±2.34） of simvastatin and simvastatin acid in the test group were significantly increased（P<0.05）and CL decreased significantly（P<0.05）compared with the control group.Conclusions:The method is found to be simple,sensitive and accurate for determining the concentration of rivaroxaban,simvastatin and simvastatin acid in rats plasma.Rivaroxaban significantly increased the absorption of simvastatin and slowed down the metabolism of simvastatin;however,simvastatin had no significant effect on the pharmacokinetic parameters of rivaroxaban.