title: Effect of drug efflux transporters on placental transport of antiretroviral agent abacavir.
abstract: Abacavir is as a frequent part of combination antiretroviral therapy used in pregnant women. The aim of this study was to investigate, using in vitro, in situ and ex vivo experimental approaches, whether the transplacental pharmacokinetics of abacavir is affected by ATP-binding cassette (ABC) efflux transporters functionally expressed in the placenta: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), multidrug resistance-associated protein 2 (ABCC2) and multidrug resistance-associated protein 5 (ABCC5). In vitro transport assays revealed that abacavir is a substrate of human ABCB1 and ABCG2 transporters but not of ABCC2 or ABCC5. In addition, in situ experiments using dually perfused rat term placenta confirmed interactions of abacavir with placental Abcb1/Abcg2. In contrast, uptake studies in human placental villous fragments did not reveal any interaction of abacavir with efflux transporters suggesting a large contribution of passive diffusion and/or influx mechanisms to net transplacental abacavir transfer.
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Heyrovskeho 1203, 50005 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, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Greenwood
authors.affiliation: Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Heyrovskeho 1203, 50005 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, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic. Electronic address: frantisek.staud@faf.cuni.cz.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics*; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D017208:Rats, Wistar; D000099227:Abacavir
chemical_list: D044966:Anti-Retroviral Agents; D015224:Dideoxynucleosides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000099227:Abacavir; C000715087:ABCC2 protein, human
keywords: Abacavir; Breast cancer resistance protein; HIV; Multidrug resistance-associated proteins; P-glycoprotein; Transplacental pharmacokinetics