Role of nucleoside transporters in transplacental pharmacokinetics of nucleoside reverse transcriptase inhibitors zidovudine and emtricitabine

Karbanova, Sara; Červený, Lukáš; Čečková, Martina; Ptackova, Zuzana; Jirásková, Lucie; Greenwood, Susan; Štaud, František

doi:10.1016/j.placenta.2017.10.011

Cited by 12 publications

(17 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we deduced that ENT1, but not ENT2, contributed to FTC transport in the placenta. However, Karbanova et al (6), reported that ENTs do not play a vital role in transfer of FTC across the placenta based on the observation that NBTI did not significantly inhibit FTC accumulation, results that are inconsistent with our data. We speculated that the discrepancy in the results might be attributed to the difference in the expression levels of transporters in experimental models.…”

Section: Discussioncontrasting

confidence: 99%

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Zeng

Bai

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.

show abstract

Section: Discussioncontrasting

confidence: 99%

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Zeng

Bai

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The radiolabeled compounds [ 3 H]-abacavir (0.05 or 0.1 Ci/mM), [ 3 H]-adenosine (23 Ci/mM), and [ 3 H]-thymidine (74 Ci/mM) were purchased from Moravek Biochemicals (Brea, CA); adenosine represents a model substrate of ENT1, ENT2, CNT2, and CNT3, whereas thymidine is transported by ENT1, ENT2, CNT1, and CNT3 (Molina-Arcas et al, 2009). The specific ENT inhibitor S 6 -(4-nitrobenzyl)mercaptopurine riboside (NBMPR) and the competitive inhibitors of ENTs and CNTs, uridine and adenosine (Molina-Arcas et al, 2009;Errasti-Murugarren et al, 2011), were purchased from Sigma-Aldrich (St. Louis, MO); NBMPR (0.1 mM) selectively inhibits human and rat ENT1/Ent1, whereas a concentration of 100 mM abolishes the activity of both human and rat ENT1/Ent1 and ENT2/Ent2 (Chishu et al, 2008;Sai et al, 2008;Molina-Arcas et al, 2009;Nishimura et al, 2011Nishimura et al, , 2012Karbanova et al, 2017). Pentobarbital (Nembutal) was purchased from Abbott Laboratories (Abbott Park, IL).…”

Section: Methodsmentioning

confidence: 99%

“…The human choriocarcinoma-derived BeWo cell line was purchased from the European Cell Culture Collection (Salisbury, Wiltshire, UK). Cells were cultured in Ham's F12 medium supplemented with 10% fetal bovine serum (Karbanova et al, 2017). The cells were cultured at 37°C under an atmosphere containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…For uptake experiments, BeWo cells were seeded at a density of 3.5 Â 10 5 on 24-well culture plates (TPP Techno Plastic Products, Trasadingen, Switzerland) and cultured for 3 days until confluence with daily medium replacement. Uptake experiments were performed as previously described, with modifications (Yamamoto et al, 2007;Karbanova et al, 2017). In brief, experiments were performed in 0.25 ml of control (Na + -containing) buffer (140 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl 2 , 0.8 mM MgSO 4 , 5 mM glucose, and 25 mM Tris) or Na + -free buffer (Na + was replaced by N-methyl-D-glucamine).…”

Section: Methodsmentioning

confidence: 99%

“…Ex Vivo Accumulation Studies in Fresh Villous Fragments from Human Placenta. Ex vivo analysis of [ 3 H]-abacavir uptake by the human placenta was performed using the method of accumulation in fresh villous fragments of human placentas at term (Atkinson et al, 2006;Greenwood and Sibley, 2006;Neumanova et al, 2015;Karbanova et al, 2017). In brief, placentas were collected at term after uncomplicated pregnancies (after 38-40 weeks of gestation) from women at St. Mary's Hospital (Manchester, UK) or from the University Hospital (Hradec Kralove, Czech Republic) after receiving the women's written informed consent as approved by the Local Research Ethics Committees (REC 12/NW/0574 and 201006S15P, respectively).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta

et al. 2018

Self Cite

View full text Add to dashboard Cite

Abacavir is a preferred antiretroviral drug for preventing mother-to-child human immunodeficiency virus transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, equilibrative nucleoside transporters (ENTs, ) and/or Na-dependent concentrative nucleoside transporters (CNTs, ), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using the choriocarcinoma-derived BeWo cell line, human fresh villous fragments, and microvillous plasma membrane (MVM) vesicles. Using endogenous substrates of nucleoside transporters, [H]-adenosine (ENTs, CNT2, and CNT3) and [H]-thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells, whereas experiments in the villous fragments and MVM vesicles, representing a model of the apical membrane of a syncytiotrophoblast, revealed only ENT1 activity. When testing [H]-abacavir uptakes, we showed that of the nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na-dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [H]-abacavir placental transport. Finally, we quantified the expression of in first- and third-trimester placentas, revealing that is the dominant isoform. Neither nor expression changed over the course of placental development, but there was considerable interindividual variability in their expression. Therefore, drug-drug interactions and the effect of interindividual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy.

show abstract

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Hau

Wright

Cherrington

2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small‐molecule drug–drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non‐nucleoside/non‐nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD‐1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off‐target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration.

show abstract

Role of nucleoside transporters in transplacental pharmacokinetics of nucleoside reverse transcriptase inhibitors zidovudine and emtricitabine

Cited by 12 publications

References 48 publications

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Contact Info

Product

Resources

About