title: Secretory transport of ranitidine and famotidine across Caco-2 cell monolayers.
abstract: The secretory transport of the H(2)-antagonists, ranitidine and famotidine, across Caco-2 cell monolayers was found to be a saturable process. Both drugs exhibited greater permeability in the basolateral (BL) to apical (AP) direction than in the AP to BL direction, indicating apically directed secretion; BL to AP transport was inhibited by P-glycoprotein (P-gp) inhibitors verapamil and cyclosporin A. The cellular uptake of ranitidine across the BL membrane was saturable and temperature dependent, indicative of carrier-mediated transport. The K(m) and V(max) for the uptake process were estimated to be 66.9 mM and 20.9 nmol/mg of protein/min, respectively. The uptake of [(14)C]ranitidine across the BL membrane was inhibited by unlabeled ranitidine and structurally diverse organic cations. The tetraethylammonium (TEA)-sensitive organic cation transporters are not involved in the uptake of ranitidine and famotidine across the BL membrane of Caco-2. This conclusion was based on the evidence that functionally active TEA-sensitive organic cation transporters did not exist in the BL membranes of the Caco-2 cells, whereas the functionally active TEA-sensitive organic cation transporter(s) in LLC-PK(1) cells did not contribute to the transport of ranitidine or famotidine across the cell monolayers. Thus, we conclude that the secretory transport of ranitidine and famotidine across Caco-2 cell monolayers is mediated by 1) a carrier in the BL membrane that is distinct from the TEA-sensitive organic cation transporter(s) and 2) P-gp in the apical membrane.
authors.affiliation: Division of Drug Delivery and Disposition, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Chee
authors.initials: C
authors.lastname: Ng
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.forename: Dhiren R
authors.initials: DR
authors.lastname: Thakker
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D015738:Famotidine / Q000378:metabolism*; D006635:Histamine H2 Antagonists / Q000378:metabolism*; D006801:Humans; D018374:LLC-PK1 Cells; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D011899:Ranitidine / Q000378:metabolism*; D013552:Swine; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D006635:Histamine H2 Antagonists; D027701:Organic Cation Transport Proteins; D013757:Tetraethylammonium Compounds; D015738:Famotidine; D011899:Ranitidine