title: Impact of carriers in oral absorption: Permeation across Caco-2 cells for the organic anions estrone-3-sulfate and glipizide.
abstract: Carriers may mediate the permeation across enterocytes for drug substances being organic anions. Carrier mediated permeation for the organic anions estrone-3-sulfate (ES) and glipizide across Caco-2 cells were investigated kinetically, and interactions on involved carriers evaluated. Initial uptakes (P(UP)) at apical and basolateral membranes, apparent permeabilities (P(APP)) and corresponding intracellular end-point accumulations (P(EPA)) of radioactive labeled compounds were studied. Possible effects of other anionic compounds were investigated. Apical P(UP) and absorptive P(APP) for ES were inhibited and its absorptive P(EPA) prevented in presence of the investigated organic anions and apical P(UP) was saturable with K(m) 23microM. Basolateral P(UP) and exsorptive P(APP) were inhibited, its exsorptive P(EPA) was prevented, and basolateral P(UP) and exsorptive P(APP) were saturable with K(m) 44microM and 38microM, respectively. BCRP inhibition affected both absorptive an exsorptive P(EPA) and P(APP) for ES. Glipizide apical P(UP) and absorptive P(APP) were not inhibitable. Basolateral P(UP) for glipizide was inhibitable, its P(EPA) prevented, and P(UP) was saturable with K(m) 56microM, but exsorptive P(APP) was not affected. Carrier mediated exsorption kinetics for ES are seen at both apical and basolateral membranes, resulting in predominant exsorption despite presence of absorptive carrier(s). Carrier mediated basolateral P(UP) for glipizide was observed, but glipizide P(APP) was not described by carrier kinetics. However, glipizide is affecting exsorption for ES, due to interactions on basolateral carrier. The study confirms that estrone-3-sulfate can be used to characterize anionic carrier kinetics. Furthermore it is suggested that estrone-3-sulfate may be used to identify compounds which may interact on anionic carriers.
authors.affiliation: Molecular Biopharmaceutics, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Luise K
authors.initials: LK
authors.lastname: Gram
authors.forename: Gerda Marie
authors.initials: GM
authors.lastname: Rist
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
authors.forename: Bente
authors.initials: B
authors.lastname: Steffansen
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004970:Estrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005913:Glipizide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D004966:Estrogens, Conjugated (USP); D007004:Hypoglycemic Agents; D004970:Estrone; C017296:estrone sulfate; D005913:Glipizide