Effect of Shuxuetong injection on anticoagulant effect of warfarin in rats

Abstract

To explore the effect of Shuxuetong injection on the pharmacodynamics and pharmacokinetics of warfarin in rats, and to provide reference for rational drug use. In studies on the single dose of warfarin, Wistar rats were randomly divided into four groups： blank control group(group A), Shuxuetong injection group(group B), warfarin control group(group C), and warfarin+Shuxuetong injection group(group D). In studies on the steady state of warfarin, Wistar rats were randomly divided into warfarin control group(group E) and warfarin+Shuxuetong injection group(group F). To investigate the pharmacodynamic effect of Shuxuetong injection on warfarin, prothrombin time(PT) and activated partial thromboplastin time(APTT) were measured by coagulation analyzer, and international normalized ratio(INR) was calculated. To investigate the pharmacokinetic effect of Shuxuetong injection on warfarin, the blood concentrations of S-warfarin and R-warfarin were determined by UPLC-MS/MS combined with technology of chiral chromatographic column, and the related pharmacokinetic parameters were calculated accordingly. The results on the single dose of warfarin showed that Shuxuetong injection markedly increased PT, INR(P<0.01), and APTT(P<0.05). Meanwhile, when Shuxuetong injection was co-administrated with warfarin, it significantly increased PT, INR(P<0.01), and APTT(P<0.05) as compared with warfarin control group. In addition, increased pharmacokinetic parameters including Cmax, AUC0-t and AUC0-∞, prolonged t1/2, and decreased CL/F were observed for S-warfarin and R-warfarin. The results of the steady state of warfarin suggested that Shuxuetong injection significantly increased PT and INR of warfarin(P<0.01), and elevated the plasma concentrations of S-warfarin and R-warfarin when co-administrated with warfarin. These findings indicated that Shuxuetong injection had anticoagulant effect, and would produce pharmacodynamics synergistic action when it was co-administrated with warfarin. Shuxuetong injection also decelerated the metabolism of warfarin, and resulted in pharmacokinetics interaction. Therefore, Shuxuetong injection could significantly increase anticoagulant effect of warfarin, indicating that the combination use of these two drugs should be refrained in order to avoid the risk of bleeding in clinical application. If they need to be used in combination, special attention should be paid to ensure the safety of patients.