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Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine
M. Ceckova, J. Reznicek, Z. Ptackova, L. Cerveny, F. Müller, M. Kacerovsky, MF. Fromm, JD. Glazier, F. Staud,
Language English Country United States
Document type Journal Article
NLK
Free Medical Journals
from 1972 to 6 months ago
Freely Accessible Science Journals
from 1995 to 6 months ago
PubMed Central
from 1972 to 1 year ago
Europe PubMed Central
from 1972 to 6 months ago
Open Access Digital Library
from 1972-01-01
Open Access Digital Library
from 1972-01-01
PubMed
27401571
DOI
10.1128/aac.00648-16
Knihovny.cz E-resources
- MeSH
- ATP-Binding Cassette Transporters metabolism MeSH
- Biological Transport physiology MeSH
- Cell Line MeSH
- Madin Darby Canine Kidney Cells MeSH
- Rats MeSH
- Lamivudine metabolism MeSH
- Humans MeSH
- ATP Binding Cassette Transporter, Subfamily B metabolism MeSH
- Placenta metabolism MeSH
- Rats, Wistar MeSH
- Organic Cation Transport Proteins metabolism MeSH
- Multidrug Resistance-Associated Proteins metabolism MeSH
- Dogs MeSH
- Pregnancy MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Dogs MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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.
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