Collett, Andrew, Higgs, Norman B., Sims, E., Rowland, M. and Warhurst, Geoff (1999) Modulation of the Permeability of H2 Receptor Antagonists Cimetidine and Ranitidine by P-Glycoprotein in Rat Intestine and the Human Colonic Cell Line Caco-21. The Journal of pharmacology and experimental therapeutics, 288 (1). p. 178. ISSN 0022-3565
Metadata only available from this repository.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 /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.
Item Type: | Article |
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Subjects: | Q Science > QH Natural history > QH301 Biology |
Schools: | School of Applied Sciences |
Related URLs: | |
Depositing User: | Cherry Edmunds |
Date Deposited: | 26 Aug 2009 09:16 |
Last Modified: | 28 Aug 2021 10:50 |
URI: | http://eprints.hud.ac.uk/id/eprint/5471 |
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