Paracellular drug transport across intestinal epithelia: influence of charge and induced water flux

The influence of drug charge and transepithelial water flux on passive para cellular drug transport was investigated in Caco-2 cell monolayers and mt i leal mucosa in vitro. Three small hydrophilic compounds with different net charges (creatinine, erythritol and foscarnet) were used as model drugs. A hypotonic glucose-rich solution was applied apically to induce epithelial a bsorption of water. In the Caco-2 monolayers, permeability to creatinine (p ositively charged) was 25-fold greater than to foscarnet (negatively charge d), indicating a pronounced cation selective paracellular permeability. Dur ing apical exposure to the hypotonic glucose-rich solution, transport of al l model drugs increased in both the absorptive and secretory directions. Th is enhanced transport coincided with a decrease in transepithelial resistan ce. Further, fluorescence and transmission electron microscopy indicated di latations of the paracellular spaces but no damage to the cell membranes. T hese findings suggested that the enhancement in drug transport was attribut able to increased paracellular tight junction permeability rather than to " solvent drag". In the ileal segments, mucosal exposure to the hypotonic glu cose-rich solution had no effect on transepithelial resistance and only a m arginal increase in drug transport was observed. Taken together, the modest absorption enhancement demonstrated in the in vitro models agrees with res ults obtained in vivo, supporting the conclusion that a mon pronounced disr uption of the tight junction barrier than that obtained through stimulation of epithelial absorption of water is required for efficient enhancement of paracellular intestinal drug absorption. (C) 1999 Elsevier Science B.V. Al l rights reserved.