Modulation of the permeability of H-2 receptor antagonists cimetidine and ranitidine by P-glycoprotein in rat intestine and the human colonic cell line Caco-2

The influence of secretory transporters on intestinal permeability characte ristics of the H-2 receptor antagonists ranitidine and cimetidine was studi ed in Caco-2 monolayers and rat intestinal mucosa mounted in Ussing chamber s. Both drugs exhibited vectorial transport across rat ileum with significa ntly greater (2-4-fold) permeability in the serosal-to-mucosal than the muc osal-to-serosal direction, indicative of net mucosal secretion. Mucosal ran itidine secretion was also observed in rat distal colon, although to a less er degree. Ileal ranitidine secretion was concentration dependent and signi ficantly reduced by the P-glycoprotein (P-gp) substrates verapamil and cycl osporin. In contrast, probenicid, an inhibitor of the multidrug-related pro tein, had no effect on ranitidine permeability. The paracellular marker man nitol showed no evidence of asymmetric permeability or sensitivity to P-gp inhibitors. Significant expression of P-gp protein in rat intestinal epithe lial cells was confirmed by immunoblotting. Caco-2 monolayers, which overex press P-gp, also showed asymmetric permeability of ranitidine and cimetidin e. In this model, ranitidine permeability in the mucosal-to-serosal directi on decreased by approximate to 95% as monolayer resistance increased from 1 50 to 500 Omega/cm(2), indicating a primarily paracellular route of transpo rt. However, serosal-to-mucosal permeability was insensitive to resistance changes, consistent with a primarily transcellular route in this direction. These data indicate that ranitidine and cimetidine can act as substrates f or intestinal P-gp and suggest that the balance between absorptive and secr etory mechanisms as a factor in determining intestinal absorption needs to be a routine consideration even for compounds expected to have a predominan tly paracellular route of absorption.