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Vol. 288, Issue 1, 171-178, January 1999
Department of Medicine, University of Manchester School of
Medicine, Hope Hospital, Salford, England (A.C., N.B.H., E.S., G.W.);
and
School of Pharmacy and Pharmaceutical Sciences, University of
Manchester, Manchester, England (M.R.)
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.
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