Saturable transport of H-2-antagonists ranitidine and famotidine across Caco-2 cell monolayers

The purpose of this study was to investigate the mechanism by which the Hz- antagonists ranitidine and famotidine interacted with the paracellular spac e during their transport across Caco-2 cell monolayers. Transport experimen ts with ranitidine and famotidine across Caco-2 cell monolayers were perfor med to determine the apical-to-basolateral flux at various concentrations. Kinetic analysis of the transport data showed that ranitidine and famotidin e were transported by both saturable and nonsaturable processes. Na+,K+-ATP ase inhibitor ouabain and metabolic inhibitors sodium azide + 2-deoxy-D-glu cose did not affect ranitidine transport, suggesting that the active transp ort was not involved. Famotidine and some other guanidine-containing compou nds, e.g., guanethidine, Arg-Gly, L-arginine methyl ester, and L-argininami de, inhibited the transport of ranitidine, whereas other guanidine-containi ng compounds with an additional negative charge, e.g., L-arginine, did not. 2,4,6-Triaminopyrimidine (TAP), an inhibitor of paracelluar cationic condu ctance, also inhibited the transport of both ranitidine and famotidine. On the basis of these results, it is proposed that the saturable transport of ranitidine and famotidine across Caco-2 cell monolayers appears to be via a facilitated diffusion process mediated by the paracellular anionic sites. This mechanism is consistent with the observation that ranitidine and famot idine caused a concentration-dependent increase in transepithelial electric al resistance (TEER) across Caco-2 cell monolayers, presumably by blocking the paracellular anionic sites and thus inhibiting the flux of cations (e.g ., Na+).