title: Application and limitation of inhibitors in drug-transporter interactions studies.
abstract: The objective of the present study was to investigate the reliability of transporter inhibitors in the elucidation of drug-transporter interactions when multiple transporters are present in a test system. The bidirectional permeabilities of digoxin, estrone-3-sulfate (E3S), and sulfasalazine, substrates of P-gp, BCRP/MRP2 and unspecified efflux transporters, respectively, were examined in Caco-2 and MDR-MDCK cells in the absence and presence of transporter inhibitors: CsA (P-gp), FTC (BCRP) and MK571 (MRP). Digoxin showed significant efflux ratios (ER) in both Caco-2 (ER=17) and MDR-MDCK (ER=120), whereas E3S and sulfasalazine only showed significant efflux in Caco-2 (ER=15 and 88, respectively) but not in MDR-MDCK cells (ER=1.1 and 1.3, respectively). CsA at 10 microM showed complete inhibition of digoxin efflux, partial inhibition of E3S efflux and no effect on sulfasalazine efflux. FTC and MK571 had different inhibitory effects on the efflux of these compounds. The present study shows evidence of the functional expression of multiple efflux transporter systems in Caco-2 cells. Although the use of Caco-2 cells and selected inhibitors of efflux transporters can provide useful mechanistic information on drug-drug interactions involving efflux transporters, the potential cross-reaction of inhibitors with multiple transporters makes it difficult to discern the role of individual transporters in drug transport or drug-drug interactions.
authors.affiliation: Absorption Systems 436 Creamery Way, Suite 600 Exton, PA 19341, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Strab
authors.forename: Paula
authors.initials: P
authors.lastname: Kardos
authors.forename: Chrissa
authors.initials: C
authors.lastname: Ferguson
authors.forename: Jibin
authors.initials: J
authors.lastname: Li
authors.forename: Albert
authors.initials: A
authors.lastname: Owen
authors.forename: Ismael J
authors.initials: IJ
authors.lastname: Hidalgo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004077:Digoxin / Q000493:pharmacokinetics; D004285:Dogs; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012460:Sulfasalazine / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016572:Cyclosporine; D004077:Digoxin; D004970:Estrone; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011422:Propionates; D011804:Quinolines; D012460:Sulfasalazine; C116614:ABCG2 protein, human; C059141:verlukast; C010522:tryptoquivaline; C017296:estrone sulfate