Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gahir, Sarabjit S.; Piquette-Miller, Micheline

doi:10.1124/dmd.110.034983

Cited by 18 publications

(9 citation statements)

References 36 publications

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“…Interestingly, while we found significant differences in the placental expression of transporters between the PXR +/+ and PXR −/− fetal genotypes, these differences were not as great as those seen in our previous study [ 33 ]. For instance, while we previously saw a 12-fold higher expression of Abcb1a in the placenta of PXR −/− dams as compared to PXR +/+ dams, only a two-fold difference was seen in the placental expression between the PXR +/+ and PXR −/− fetuses.…”

Section: Discussioncontrasting

confidence: 87%

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The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice

Gahir

Piquette-Miller

2017

Pharmaceutics

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Lopinavir (LPV), an antiretroviral protease inhibitor frequently prescribed in HIV-positive pregnancies, is a substrate of Abcb1 and Abcc2. As differences in placental expression of these transporters were seen in Pregnane X Receptor (PXR) −/− mice, we examined the impact of placental transporter expression and fetal PXR genotype on the fetal accumulation of LPV. PXR +/− dams bearing PXR +/+, PXR +/−, and PXR −/− fetuses were generated by mating PXR +/− female mice with PXR +/− males. On gestational day 17, dams were administered 10 mg/kg LPV (i.v.) and sacrificed 30 min post injection. Concentrations of LPV in maternal plasma and fetal tissue were measured by LC-MS/MS, and transporter expression was determined by quantitative RT-PCR. As compared to the PXR +/+ fetal units, placental expression of Abcb1a, Abcc2, and Abcg2 mRNA were two- to three-fold higher in PXR −/− fetuses (p < 0.05). Two-fold higher fetal:maternal LPV concentration ratios were also seen in the PXR +/+ as compared to the PXR −/− fetuses (p < 0.05), and this significantly correlated to the placental expression of Abcb1a (r = 0.495; p < 0.005). Individual differences in the expression of placental transporters due to genetic or environmental factors can impact fetal exposure to their substrates.

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Section: Discussioncontrasting

confidence: 87%

“…We have previously demonstrated a tissue-specific role for PXR in mice [ 33 ]. Several PXR target genes (Abcb1a, Abcc1-3, and Abcg2) were found to be elevated in the placenta in PXR null mice, with dramatically higher levels of placental transporters in the PXR −/− mice as compared to the PXR +/+ mice.…”

Section: Introductionmentioning

confidence: 99%

The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice

Gahir

Piquette-Miller

2017

Pharmaceutics

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“…PXR is Mdr1 and Cyp3a2's primary transcriptional regulator, so not surprisingly, its hepatic protein concentrations positively correlated with hepatic Mdr1 and Cyp3a2 concentrations. It is conceivable that a similar regulatory effect may be at work in the placenta, although recent work with PXR knockout mice has drawn the role of placental PXR in placental transporter regulation into question (Gahir and Piquette-Miller, 2011).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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ABSTRACT:Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocininduced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1-and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.

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“…Following PXR activation by PCN, no significant change was observed in the expression of ABC transporters in the placenta unlike liver where a 30-fold increase was observed. This suggested a tissue specific role of PXR with respect to regulation of the ABC transporters (277). …”

Section: Hormones Cytokines and Placental Abc Transportersmentioning

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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Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Cited by 18 publications

References 36 publications

The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice

The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

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