title: Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine.
abstract: Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent Km of 4.21 mM and Vmax of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Reznicek
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Ptackova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, Charles University in Prague, Hradec Kralove, Czech Republic.
authors.forename: Marian
authors.initials: M
authors.lastname: Kacerovsky
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
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, United Kingdom.
authors.forename: Jocelyn D
authors.initials: JD
authors.lastname: Glazier
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic frantisek.staud@faf.cuni.cz.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D019259:Lamivudine / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D019259:Lamivudine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027701:Organic Cation Transport Proteins; C000715087:ABCC2 protein, human