Modulation of CYP3A enzyme activity by diosmin and its consequence on carbamazepine pharmacokinetics in rats.

Abstract

Diosmin is a widely used flavonoid for the treatment of varicose veins and hemorrhoids. Epileptic patients with hemorrhoids and varicose veins may use diosmin along with carbamazepine (CBZ) therapy, which leads to pharmacokinetic interaction between diosmin and CBZ. Therefore, the present study was performed to evaluate the effect of diosmin on the pharmacokinetics of CBZ in rats. Diosmin-mediated altered CYP3A enzyme activity in human and rat liver microsomes was examined using CYP3A dependent erythromycin N-demethylase assay. Further, an in vivo pharmacokinetic study of oral administered CBZ in rats with and without diosmin pretreatment was performed. The CYP3A enzyme activity in human and rat liver microsomes was significantly (p < 0.05) decreased by diosmin when compared to control. Pretreatment with diosmin significantly (p < 0.05) enhanced maximum plasma concentration (C max), area under the curve (AUC), and half life (t 1/2), while significantly (p < 0.05) decreased elimination rate constant (k el) and apparent oral clearance (CL/F) of CBZ as compared to control rats. On the other hand, C max, AUC, and t 1/2 of carbamazepine 10, 11-epoxide (CBZE) were significantly (p < 0.05) decreased after diosmin pretreatment. Furthermore, diosmin pretreatment significantly (p < 0.05) decreased metabolic ratios of C max and AUC when compared to control, suggesting reduced formation of CBZ to CBZE. The results suggest that diosmin pretreatment might have inhibited CYP3A-mediated metabolism of CBZ. Accordingly, caution should be taken when diosmin is used in combination with therapeutic drugs metabolized by CYP3A enzyme in addition to CBZ.