Enhanced Oral Bioavailability of Diltiazem by the Influence of Gallic Acid and Ellagic Acid in Male Wistar Rats: Involvement of CYP3A and P-gp Inhibition
The oral bioavailability of diltiazem is very low due to rapid first pass metabolism in liver and intestine. The purpose of the study was to investigate the effect of gallic acid and ellagic acid on intestinal transport and oral bioavailability of diltiazem in rats. The intestinal transport and permeability of diltiazem was evaluated byin vitronon-everted sac method andin situsingle pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study. The intestinal transport and apparent permeability of diltiazem were significantly enhanced in duodenum, jejunum, and ileum of gallic and ellagic acid-treated groups. The effective permeability of diltiazem was significantly enhanced in ileum part of gallic and ellagic acid-treated groups. When compared with control group, the presence of these two phytochemicals significantly enhanced the area under plasma concentration-time curve and the peak plasma concentration of diltiazem (Cmax). Gallic acid and ellagic acid significantly increased the bioavailability of diltiazem due to the inhibition of both CYP3A-mediated metabolism and P-glycoprotein-mediated efflux in the intestine and/or liver. Based on these results, the clinical experiments are warranted for the confirmation to reduce the dose of diltiazem when concomitantly administered with these phytochemicals.