Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

Ceckova M, Reznicek J, Ptackova Z, Cerveny L, Müller F, Kacerovsky M, Fromm M, Glazier JD, Staud F (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Antimicrobial Agents and Chemotherapy American Society for Microbiology

Book Volume: 60

Pages Range: 5563-72

Journal Issue: 9

DOI: 10.1128/AAC.00648-16

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 with CRIS profile

Fabian Müller Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ) University of Manchester GB United Kingdom (GB)

How to cite

APA:

Ceckova, M., Reznicek, J., Ptackova, Z., Cerveny, L., Müller, F., Kacerovsky, M.,... Staud, F. (2016). Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine. Antimicrobial Agents and Chemotherapy, 60(9), 5563-72. https://doi.org/10.1128/AAC.00648-16

MLA:

Ceckova, Martina, et al. "Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine." Antimicrobial Agents and Chemotherapy 60.9 (2016): 5563-72.

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