Effect of Diosmin on Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Rats

Background and Objective Rivaroxaban, a direct oral anticoagulant, has become the first-line therapy medicine to prevent and treat Venous Thromboembolism (VTE). Patients with femoropopliteal venous thrombosis may use rivaroxaban along with diosmin. Rivaroxaban is the substrate of CYP3A4 and P-glycoprotein (P-gp), but diosmin is the inhibitor. The combination might lead to Drug-drug Interaction (DDI). The aim of this study was to assess the effect of diosmin on the pharmacokinetics and pharmacodynamics of rivaroxaban in rats.Methods Plasma concentration of rivaroxaban in the absence or presence of diosmin groups was determined by High-performance Liquid Chromatography (HPLC). Pharmacokinetics parameters were calculated and used to evaluate pharmacokinetics interactions. Anticoagulation was investigated by Prothrombin Time (PT), International Normalized Ratio (INR), and Activated Partial Thromboplastin Time (APTT). Antithrombotic efficacy was investigated by the length of tail thrombosis, the content levels of Interleukin-1 beta (IL-1 beta) and D-dimer (D-D) in rats, and histopathological sections in the tail thrombosis model.Results Maximum concentration (Cmax), 0-t Area Under the Curve (AUC0-t), 0-infinity Area Under the Curve (AUC0-infinity) of rivaroxaban increased significantly in the combination group. PT, INR, and APPT in the combination group exhibited an increase compared to the Rivaroxaban group. Simultaneously, the length of tail thrombosis and levels of IL-1 beta and D-D were significantly reduced. Significant improvement of tissue histology in tail thrombosis could be observed.Conclusion Taken together, diosmin could significantly affect the pharmacokinetics and pharmacodynamics of rivaroxaban, and enhance anticoagulant and antithrombotic efficacy in rats. More attention should be paid to avoid harmful DDI in the clinic.