INTRODUCTION: Zidovudine (AZT) and emtricitabine (FTC) are effective and well tolerated antiretroviral drugs, routinely used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in their transfer from mother to fetus are not fully elucidated. Since both drugs are nucleoside analogues, we hypothesized that the mechanisms of their transplacental passage might include equilibrative nucleoside transporters, ENT1 and/or ENT2. METHODS: To address this issue, we performed in vitro accumulation assays in the BeWo placental trophoblast cell line, ex vivo uptake studies in fresh villous fragments isolated from human placenta and in situ dually perfused rat term placenta experiments. RESULTS: Applying this complex array of methods, we did not prove that ENTs play a significant role in transfer of AZT or FTC across the placenta. DISCUSSION: We conclude that the transplacental passage of AZT and FTC is independent of ENTs. Disposition of either compound into the fetal circulation should thus not be affected by ENT-mediated drug-drug interactions or placental expression of the transporters.
- MeSH
- ekvilibrační proteiny přenášející nukleosidy metabolismus MeSH
- emtricitabin farmakokinetika MeSH
- inhibitory reverzní transkriptasy farmakokinetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- placenta metabolismus MeSH
- potkani Wistar MeSH
- těhotenství MeSH
- zidovudin farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Zidovudine (AZT) is one of the most frequently used antiretroviral drugs in prevention of perinatal transmission of HIV. However, safety concerns on AZT use in pregnancy still persist as severe side effects are associated with AZT exposure in children. In our study we aimed to contribute to current knowledge on AZT transplacental transport and to evaluate potential involvement of the main human drug efflux ATP-binding cassette (ABC) transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins 2 and 5 (ABCC2 and ABCC5) in the disposition of AZT between mother and fetus. In order to elucidate this issue we investigated the effect of selected ABC transporters on AZT transepithelial transport across MDCKII cell monolayers. In addition we used the in situ method of dually perfused rat term placenta to further study the role of ABC transporters in AZT transplacental transport. In vitro studies revealed significant effect of ABCB1 and ABCG2 on AZT transport which was subsequently confirmed also on organ level. Lamivudine, an antiretroviral agent commonly co-administered with AZT, did not affect ABC transporter-mediated AZT transfer.
- MeSH
- ABC transportéry antagonisté a inhibitory metabolismus MeSH
- akridiny farmakologie MeSH
- buňky MDCK MeSH
- indomethacin farmakologie MeSH
- lamivudin farmakologie MeSH
- látky proti HIV farmakokinetika MeSH
- lékové interakce MeSH
- placenta metabolismus MeSH
- potkani Wistar MeSH
- psi MeSH
- techniky in vitro MeSH
- těhotenství MeSH
- tetrahydroisochinoliny farmakologie MeSH
- zidovudin farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- dinitrofenoly toxicita MeSH
- fenobarbital farmakologie MeSH
- játra cytologie metabolismus účinky léků MeSH
- krysa rodu rattus MeSH
- kyanid draselný toxicita MeSH
- lidé MeSH
- skot MeSH
- viabilita buněk účinky léků MeSH
- zidovudin analogy a deriváty aplikace a dávkování farmakokinetika MeSH
- žluč metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- HIV infekce farmakoterapie MeSH
- lidé MeSH
- zidovudin farmakokinetika farmakologie MeSH
- Check Tag
- lidé MeSH
