Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta
Language English Country France Media print-electronic
Document type Journal Article
PubMed
32768979
DOI
10.1016/j.biopha.2020.110506
PII: S0753-3322(20)30699-5
Knihovny.cz E-resources
- Keywords
- Drug transporters, Drug–drug interactions, MRP1, Maraviroc, OATP, Placenta,
- MeSH
- Acridines pharmacology MeSH
- Madin Darby Canine Kidney Cells MeSH
- Anti-HIV Agents blood metabolism pharmacology MeSH
- Drug Interactions MeSH
- Humans MeSH
- Maraviroc blood metabolism MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors genetics metabolism MeSH
- Perfusion MeSH
- Placenta drug effects metabolism MeSH
- Placental Circulation MeSH
- Organic Anion Transporters antagonists & inhibitors genetics metabolism MeSH
- Solute Carrier Organic Anion Transporter Family Member 1B3 antagonists & inhibitors genetics metabolism MeSH
- Multidrug Resistance-Associated Proteins genetics metabolism MeSH
- Dogs MeSH
- Gene Expression Regulation MeSH
- Ritonavir pharmacology MeSH
- Pregnancy MeSH
- Tetrahydroisoquinolines pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Dogs MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- ABCB1 protein, human MeSH Browser
- Acridines MeSH
- Elacridar MeSH Browser
- Anti-HIV Agents MeSH
- Maraviroc MeSH
- multidrug resistance-associated protein 1 MeSH Browser
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Organic Anion Transporters MeSH
- Solute Carrier Organic Anion Transporter Family Member 1B3 MeSH
- Multidrug Resistance-Associated Proteins MeSH
- Ritonavir MeSH
- SLCO1A2 protein, human MeSH Browser
- SLCO1B3 protein, human MeSH Browser
- Tetrahydroisoquinolines MeSH
Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux.
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