Impact of carriers in oral absorption: Permeation across Caco-2 cells for the organic anions estrone-3-sulfate and glipizide

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 (PUP) at apical and basolateral membranes, apparent permeabilities (PAPP) and corresponding intracellular end-point accumulations (PEPA) of radioactive labeled compounds were studied. Possible effects of other anionic compounds were investigated. Apical PUP and absorptive PAPP for ES were inhibited and its absorptive PEPA prevented in presence of the investigated organic anions and apical PUP was saturable with Km 23 μM. Basolateral PUP and exsorptive PAPP were inhibited, its exsorptive PEPA was prevented, and basolateral PUP and exsorptive PAPP were saturable with Km 44 μM and 38 μM, respectively. BCRP inhibition affected both absorptive an exsorptive PEPA and PAPP for ES. Glipizide apical PUP and absorptive PAPP were not inhibitable. Basolateral PUP for glipizide was inhibitable, its PEPA prevented, and PUP was saturable with Km 56 μM, but exsorptive PAPP 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 PUP for glipizide was observed, but glipizide PAPP 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.