Modulation of the permeability of H2 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 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 approximately 95% as monolayer resistance increased from 150 to 500 Omega/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.
Collett
A
A
Department of Medicine, University of Manchester School of Medicine, Hope Hospital, Salford, England, UK.
Higgs
N B
NB
Sims
E
E
Rowland
M
M
Warhurst
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002927:Cimetidine / Q000493:pharmacokinetics*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D019450:Genes, MDR / Q000502:physiology; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D011899:Ranitidine / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006635:Histamine H2 Antagonists; D002927:Cimetidine; D011899:Ranitidine