Effects of Hesperidin or Epigallocatechin gallate on the Oral Bioavailability of Verapamil in Rats

Abstract

Favonoids can modulate the P-glycoprotein (P-gp) and microsomal cytochrome P450 isoenzymes (CYP) 3A. The F of many drugs are low which contirbute highly to the first-pass effect mainly caused by phase 1 and phase 2 metabolism, and the members of ATP-binding cassettte (ABC) superfamily mediated-efflux by P-gp in the intestine and the liver. Thuse this study investigated the pharmacokinetics of intravenous (i.v.) or oral verapamil in rats in order to examine the effects of P-gp and CYP 3A by hesperidin or epigallocatechin gallate (EGCG) on the absolute oral bioavailability of verapamil. Hesperidin and epigallocatechin gallate (EGCG), flavonoids, are suggested to inhibit P-gp and CYP3A in vitro. A single i.v. (3 mg/kg) or oral (9 mg/kg) dose of verapamil was administered to rats with or without oral adminitration of hesperidin or EGCG at a dose of 3 or 15 mg/kg, respectively, 30 min prior to the oral administration of verapamil. Plasma concentrations of verapamil and norverapamil well determined using an HPLC analysis with a fluorescence detector. Hesperidin caused significantly (p < 0.01) greater the total area under the plasma concentration?time curve (AUC) of verapamil by 71.1?96.8% and the peak concentration (Cmax) of verapamil by 98.3?105.2%, and the presence of hesperidin was increased the terminal half-life (t1/2) of verapamil but not significantly. Hesperidin significantly (p < 0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6?49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (Tmax) and the elimination rate constant (Kel) of verapamil by hesperidin. The AUC and Cmax of norverapamil were significantly (p < 0.05) higher by hesperidin and the presence of hesperidin was increased the terminal half-life (t1/2) of verapamil but not significantly, but hesperidin decreased the metabolite-parent ratio (MR) of norverapamil. There was no significant change in the Tmax and the Kel of norverapamil by hesperidin. EGCG caused significantly (p < 0.01) greater the AUC of verapamil by 85.2?127% and the Cmax by 102?136%, and the presence of EGCG was increased the t1/2 of norverapamil but not significantly. The presence of EGCG significantly (p < 0.01) decreased the CL/F of verapamil by 46.0?55.9%. The enhanced oral bioavailability of verapamil might be due to the decreased efflux and metabolism of verapamil in the intestine. There was no significant change in the Tmax and the Kel of norverapamil by EGCG. Compared to the oral control group, the presence of EGCG significantly (p < 0.05) increased the AUC of norverapamil by 72.9?93.9% and the Cmax by 65.3?72.9%, and the presence of EGCG was increased the t1/2 of norverapamil, but the metabolite-parent ratio (MR) of norverapamil by EGCG decreased but is not significantly. There was no significant change in the Tmax and the Kel of norverapamil by EGCG. The enhanced F of verapamil was observed in rats in combination by natural flavonoids, hesperidin or EGCG in this study. It is possible that these natural flovonoids could act as candidates of modulators of P-gp and/or CYP3A to improve the F of verapamil in humans. The pharmacokinetic interaction between verapamil and hesperidin or EGCG should be taken into consideration in the clinical setting.