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.
- Klíčová slova
- Drug transporters, Drug–drug interactions, MRP1, Maraviroc, OATP, Placenta,
- MeSH
- akridiny farmakologie MeSH
- buňky MDCK MeSH
- látky proti HIV krev metabolismus farmakologie MeSH
- lékové interakce MeSH
- lidé MeSH
- maravirok krev metabolismus MeSH
- nádorové buněčné linie MeSH
- P-glykoproteiny antagonisté a inhibitory genetika metabolismus MeSH
- perfuze MeSH
- placenta účinky léků metabolismus MeSH
- placentární oběh MeSH
- přenašeče organických aniontů antagonisté a inhibitory genetika metabolismus MeSH
- protein OATP1B3 antagonisté a inhibitory genetika metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika metabolismus MeSH
- psi MeSH
- regulace genové exprese MeSH
- ritonavir farmakologie MeSH
- těhotenství MeSH
- tetrahydroisochinoliny farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ABCB1 protein, human MeSH Prohlížeč
- akridiny MeSH
- Elacridar MeSH Prohlížeč
- látky proti HIV MeSH
- maravirok MeSH
- multidrug resistance-associated protein 1 MeSH Prohlížeč
- P-glykoproteiny MeSH
- přenašeče organických aniontů MeSH
- protein OATP1B3 MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům MeSH
- ritonavir MeSH
- SLCO1A2 protein, human MeSH Prohlížeč
- SLCO1B3 protein, human MeSH Prohlížeč
- tetrahydroisochinoliny MeSH
