Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs

The effects of nitric oxide (NO) donors NOC5 3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine ] and NOC12 N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine] on the permeability of 5(6)-carboxyfluorescein (CF) across the intestinal membrane were examined by an in vitro Ussing chamber method. The NO donors significantly increased the intestinal permeability of CF and their absorption-enhancing effects were concentration-dependent over the range of 0.01 to 0.1 mM. Regional differences in the absorption-enhancing effects of the NO donors were observed (colon > jejunum). The absorption-enhancing effect of NOC12 reduced as the molecular weights of compounds increased. Therefore, the degree of absorption-enhancing effect of NOC12 was dependent on the molecular weights of compounds. In the pretreatment studies with NOC12 and lactate dehydrogenase release studies, the absorption-enhancing effect of 0.1 mM NOC12 was reversible and less toxic to the colonic membrane. On the other hand, the absorption-enhancing effect of NOC12 was inhibited by the coadministration of 2-(4-carboxyphenyl) 4,4,5, 5-tetramethylimidazole-1-oxyl 3-oxide sodium salt, an NO scavenger, suggesting that NO can regulate the permeability of water-soluble drugs in the gut. Furthermore, NOC12 (0.1 and 1 mM) significantly decreased the transepithelial electrical resistance value of the colonic membrane, suggesting that the absorption-enhancing mechanism of NOC12 may be partly related to the dilation of the tight junction in the epithelium via a paracellular route. These findings suggest that NO donors may be useful to enhance the intestinal absorption of poorly absorbable drugs.