title: Role of ABCB1, ABCG2, ABCC2 and ABCC5 transporters in placental passage of zidovudine.
abstract: Zidovudine (AZT) is one of the most frequently used antiretroviral drugs in prevention of perinatal transmission of HIV. However, safety concerns on AZT use in pregnancy still persist as severe side effects are associated with AZT exposure in children. In our study we aimed to contribute to current knowledge on AZT transplacental transport and to evaluate potential involvement of the main human drug efflux ATP-binding cassette (ABC) transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins 2 and 5 (ABCC2 and ABCC5) in the disposition of AZT between mother and fetus. In order to elucidate this issue we investigated the effect of selected ABC transporters on AZT transepithelial transport across MDCKII cell monolayers. In addition we used the in situ method of dually perfused rat term placenta to further study the role of ABC transporters in AZT transplacental transport. In vitro studies revealed significant effect of ABCB1 and ABCG2 on AZT transport which was subsequently confirmed also on organ level. Lamivudine, an antiretroviral agent commonly co-administered with AZT, did not affect ABC transporter-mediated AZT transfer.
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Neumanova
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019259:Lamivudine / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D000089762:Multidrug Resistance-Associated Protein 2; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D015215:Zidovudine / Q000493:pharmacokinetics*
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D019380:Anti-HIV Agents; D000089762:Multidrug Resistance-Associated Protein 2; D044005:Tetrahydroisoquinolines; D019259:Lamivudine; D015215:Zidovudine; C083501:Elacridar; D007213:Indomethacin
keywords: breast cancer resistance protein; multidrug resistance-associated protein 2; multidrug resistance-associated protein 5; p-glycoprotein; zidovudine