Abstract
The influence of secretory transporters on intestinal permeability characteristics of the H2 receptor antagonists ranitidine and cimetidine was studied in Caco-2 monolayers and rat intestinal mucosa mounted in Ussing chambers. Both drugs exhibited vectorial transport across rat ileum with significantly greater (2–4-fold) permeability in the serosal-to-mucosal than the mucosal-to-serosal direction, indicative of net mucosal secretion. Mucosal ranitidine secretion was also observed in rat distal colon, although to a lesser degree. Ileal ranitidine secretion was concentration dependent and significantly reduced by the P-glycoprotein (P-gp) substrates verapamil and cyclosporin. In contrast, probenicid, an inhibitor of the multidrug-related protein, had no effect on ranitidine permeability. The paracellular marker mannitol showed no evidence of asymmetric permeability or sensitivity to P-gp inhibitors. Significant expression of P-gp protein in rat intestinal epithelial cells was confirmed by immunoblotting. Caco-2 monolayers, which overexpress P-gp, also showed asymmetric permeability of ranitidine and cimetidine. In this model, ranitidine permeability in the mucosal-to-serosal direction decreased by ≈95% as monolayer resistance increased from 150 to 500 Ω/cm2, indicating a primarily paracellular route of transport. 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 for intestinal P-gp and suggest that the balance between absorptive and secretory mechanisms as a factor in determining intestinal absorption needs to be a routine consideration even for compounds expected to have a predominantly paracellular route of absorption.
Footnotes
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Send reprint requests to: Dr. Geoffrey Warhurst, Department of Medicine, Clinical Sciences Building, Hope Hospital, Salford M6 8HD, UK.
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↵1 This work was supported by GlaxoWellcome Research and Development.
- Abbreviations:
- P-gp
- P-glycoprotein
- MDR
- multidrug resistance
- MRP
- multidrug-related protein
- Rt
- transepithelial electrical resistance, PD, potential difference
- TEA
- tetraethylammonium
- Received February 17, 1998.
- Accepted July 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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