IMPROVEMENT OF GASTROINTESTINAL DRUG ABSORPTION BASED ON OPENING THE TIGHT JUNCTION

Abstract

The objective of this study was to demonstrate that main factor of improvement of intestinal drug absorption by protease inhibitors was opening the Tight Junction (TJ), and to investigate the effectiveness of protease inhibitors and the mechanism by which these inhibitors expand TJ. In vitro electro-physiological study showed that all of the inhibitors tested (Bacitracin, FK448, Camostat, Gabexate) increased membrane permeability of FITC-Dextran4000 (FD-4) and decreased the membrane resistance dose-dependently in rat colon.In situ experiment, concentration of FD-4 in plasma from colonic absorption was increased at the presence of protease inhibitors. These results show that promoting effects induced by these inhibitors in colon are based on opening the TJ.Molecular weight dependency was investigated with FDs of various molecular weights.The protease inhibitors increased the permeability of the high molecular weight compounds up to 20, 000 Da.This indicates that the protease inhibitors can be used to improve poly-peptide absorption in colon. Investigating the TJ opening mechanism, we observed the effect of Gabexate was reduced by acalmodulin antagonist, W7, which indicates the contraction of actin-myosin ring work for opening. The other inhibitors, however, was unaffected by the antagonist. these findings suggest that there are at least two mechanism of the protease inhibitors to open TJ.