title: Evidence for a polarized efflux system in CACO-2 cells capable of modulating cyclosporin A transport.
abstract: The characteristics of cyclosporin A (CsA) transport across Caco-2 monolayers were investigated. CsA (0.25-5.0 microM) was transported in a time and concentration dependent manner. The total amount of apical (AP) to basolateral (BL) transport was non-linearly related to CsA concentration from 0.25 to 1 microM and was linear from about 1 to 5 microM. Average permeability coefficient (Papp) values obtained in the AP to BL direction showed CsA concentration (0.5 and 5.0 microM) dependence, whereas those of the reverse (BL to AP) process did not. Papp values for the AP to BL direction were also markedly lower. When the P-glycoprotein pump inhibitors, chlorpromazine and progesterone, were included in the transport medium we observed a significant increase in CsA (0.5 and 5.0 microM) transport from the AP to BL direction; transport was decreased in the reverse direction. This study suggests that CsA is transported across Caco-2 cells by passive diffusion, but that a polarized efflux system (presumably a P-glycoprotein pump) located at the apical membrane can attenuate the net AP to BL transport.
authors.affiliation: Drug Metabolism Department, Glaxo Inc. Research Institute, Research Triangle Park, North Carolina 27709.
authors.forename: P F
authors.initials: PF
authors.lastname: Augustijns
authors.forename: T P
authors.initials: TP
authors.lastname: Bradshaw
authors.forename: L S
authors.initials: LS
authors.lastname: Gan
authors.forename: R W
authors.initials: RW
authors.lastname: Hendren
authors.forename: D R
authors.initials: DR
authors.lastname: Thakker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000230:Adenocarcinoma; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002746:Chlorpromazine / Q000494:pharmacology; D003110:Colonic Neoplasms; D016572:Cyclosporine / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011374:Progesterone / Q000494:pharmacology; D014316:Tritium; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D014316:Tritium; D011374:Progesterone; D016572:Cyclosporine; D002746:Chlorpromazine