Influence of diosmin on the metabolism and disposition of carbamazepine in healthy subjects

Abstract

1. Carbamazepine (CBZ) is an antiepileptic drug with narrow therapeutic window and administration in humans receiving long-term therapy with diosmin (DSN) may occur, which leads to CYP3A4-mediated drug interactions. The purpose of the present study was to assess the influence of DSN on the metabolism and pharmacokinetics of CBZ in healthy volunteers.2. An open-label, sequential, two-period study was conducted in 12 healthy male volunteers. A single dose of DSN 500 mg was administered once daily for 10 days during treatment phase. A single dose of CBZ 200 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after CBZ dosing at predetermined time intervals and analyzed by LC-MS/MS.3. Treatment with DSN significantly enhanced the maximum plasma concentration (Cmax), area under the curve (AUC), half-life (t1/2) and significantly decreased the apparent oral clearance (CL/F) and elimination rate constant (Kel) of CBZ. On the other hand, treatment with DSN significantly decreased the Cmax and AUC of carbamazepine 10, 11-epoxide (CBZE). Furthermore, treatment with DSN significantly decreased the metabolite to parent ratios of Cmax and AUC, indicating the reduced metabolism of CBZ to CBZE.4. The results suggest that the altered CYP3A4 enzyme activity and pharmacokinetics of CBZ might be attributed to DSN-mediated inhibition of CYP3A4 enzyme, which indicates pharmacokinetic interaction present between DSN and CBZ. Therefore, we conclude that DSN has an inhibiting effect on the metabolism and disposition of CBZ.