Long-term administration of tenofovir or emtricitabine to pregnant rats; effect on Abcb1a, Abcb1b and Abcg2 expression in the placenta and in maternal and fetal organs

Červený, Lukáš; Neumanova, Zuzana; Karbanova, Sara; Havlova, Ivana; Štaud, František

doi:10.1111/jphp.12495

Cited by 7 publications

(3 citation statements)

References 52 publications

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“…PCR was performed using the TaqMan Universal Master Mix II without uracil-DNA glycosylase (Thermo Fisher Scientific) and predesigned TaqMan Real Time Expression PCR assays for human (h) or rat (r) SLC29A1 (Hs01085704_g1c, Rn01648953_m1) and SLC29A2 (Hs00155426_m1, Rn01479421_m1). For greater precision during the mRNA quantification of 1818 Cerveny et al target genes, data were normalized against the geometric mean of expression of two previously identified TaqMan housekeeping genes: B2M (Hs00187842_m1) and GAPDH (Hs02758991_g1) for human samples, and Ywhaz (Rn00755072_m1) and Gapdh (Rn01775763_g1) for rat samples Cerveny et al, 2016). Stable expression of both reference genes was verified before beginning the quantitative analysis.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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“…While Mdr1a expression was higher in maternal vs. fetal organs, the expression of Bcrp was comparable in both the organs. The expression of Mdr1b was higher in some maternal organs than the fetal organs (296). Petrovic et al , observed a time dependent decrease in the levels of mRNA of Bcrp 24 h post-treatment with endotoxin in rats.…”

Section: Recent Findings From Studies Involving Multiple Abc Transmentioning

confidence: 99%

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

et al. 2016

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The human placenta fulfills a variety of essential functions during prenatal life. Several ABC transporters are expressed in the human placenta, where they play a role in the transport of endogenous compounds and may protect the fetus from exogenous compounds such as therapeutic agents, drugs of abuse, and other xenobiotics. To date, considerable progress has been made toward understanding ABC transporters in the placenta. Recent studies on the expression and functional activities are discussed. This review discusses the placental expression and functional roles of several members of ABC transporter subfamilies B, C, and G including MDR1/P-glycoprotein, the MRPs, and BCRP, respectively. Since placental ABC transporters modulate fetal exposure to various compounds, an understanding of their functional and regulatory mechanisms will lead to more optimal medication use when necessary in pregnancy.

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“…For example, neurotoxicity observed in cases of neonatal hyperbilirubinemia, linked to atazanavir (ATV) exposure, displays sex differences in occurrence, raising questions regarding ATV interactions with bilirubin transporters and metabolic enzymes in the fetal and neonatal liver [31,32]. To date, limited research has focussed on understanding the expression of transporters and metabolic enzymes in the fetal brain and liver as well as placenta in the context of ART [33,34], with little consideration of fetal sex as a variable. Lamivudine (3TC), abacavir (ABC), ATV, and ritonavir (RTV) constitute an ART regimen (3TC/ABCþATV/r) used in pregnancy, with each of these drugs also recommended by the WHO as part of other first-line and second-line regimens [35].…”

Section: Introductionmentioning

confidence: 99%

Impact of in-utero antiretroviral drug exposure on expression of membrane-associated transporters in mouse placenta and fetal brain

Gilmore

Zhang

Cameron

et al. 2021

Aids

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Objective: Although antiretroviral therapy (ART) during pregnancy is effective in limiting vertical HIV transmission, adverse outcomes persist amongst uninfected children exposed to antiretroviral drugs in utero. Membrane-associated drug transporters, metabolic enzymes, and tight junction proteins play important roles in adult antiretroviral drug disposition and toxicity; however, the fetal expression of these proteins in the context of ART, and their impact on in-utero antiretroviral drug distribution remain poorly understood. This study aimed to characterize the role of these proteins in modulating in-utero antiretroviral drug exposure.Methods: Pregnant mice were exposed to an ART regimen consisting of lamivudine, abacavir, atazanavir, and ritonavir, at clinically relevant doses. Fetal brain, liver, placenta amniotic fluid, and maternal plasma were collected on gestational day 18.5 and concentration of antiretroviral drugs in fetal tissues was measured by LC/ MS/MS, whereas transporter expression was assessed by qPCR.Results: Abacavir and lamivudine were detected in fetal brain and amniotic fluid, whereas atazanavir and ritonavir were detected in amniotic fluid only. Robust mRNA expression of key transporters was observed in adult and fetal tissues, and sex differences were identified in the expression of Abcc1 and Slc29a1 in the placenta. Antiretroviral drug exposure was associated with a reduction in relative placental Abcg2, Abcc1, and Slc29a1 expression. Conclusion:These findings identify a novel effect of fetal sex and antiretroviral drug treatment on the expression of placental transporters in a mouse model, and characterize the penetration of lamivudine and abacavir into fetal brain, uncovering a potential role of transporters in modulating fetal exposure to antiretroviral drugs.

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Long-term administration of tenofovir or emtricitabine to pregnant rats; effect on Abcb1a, Abcb1b and Abcg2 expression in the placenta and in maternal and fetal organs

Abstract: Our data broaden current knowledge on safety profile of tenofovir and emtricitabine use in pregnancy. Nevertheless, further research in other mammal species, including humans, is important to fully elucidate this issue.

Cited by 7 publications

References 52 publications

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

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

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

Impact of in-utero antiretroviral drug exposure on expression of membrane-associated transporters in mouse placenta and fetal brain

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