The Role of Placental Breast Cancer Resistance Protein in the Efflux of Glyburide across the Human Placenta

Pollex, Erika; Lubetsky, Angelika; Koren, Gideon

doi:10.1016/j.placenta.2008.05.001

Cited by 90 publications

(53 citation statements)

References 15 publications

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“…Bcrp is a key transporter for the antidiabetic drug glyburide (Zhou et al, 2008). Physicians are increasingly prescribing glyburide for pregnant women with diabetes, because it does not appear to accumulate in the fetal compartment to a great extent, in large part because of Bcrp in the placenta (Pollex et al, 2008;Zhou et al, 2008). The systemic clearance of glyburide increases during pregnancy in rodents (Zhou et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

2012

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Pregnancy increases the urinary excretion of chemicals in women and rodents. It is unknown whether the enhanced clearance of drugs during pregnancy involves changes in the expression of transporters that mediate chemical secretion and reabsorption. The purpose of this study was to quantify the mRNA and protein expression of efflux transporters in kidneys from virgin and pregnant mice on gestational days 7, 11, 14, and 17 and postnatal days 1, 15, and 30 with use of quantitative polymerase chain reaction, Western blot, and immunofluorescence. Multidrug resistance protein (Mdr) 1b mRNA, multidrug resistance-associated protein (Mrp) 4 mRNA, and protein levels decreased significantly by 25-75% throughout pregnancy and lactation. Similarly, Mrp2 and multidrug and toxin extrusion transporter (Mate) 1 mRNA expression were down-regulated 20-40% during mid to late gestation but returned to control levels by postnatal day 15. In contrast, Mrp3 mRNA and protein increased 225% and 31%, respectively, at gestational day 14. Coordinated down-regulation of brush border transporters Mate1, Mrp2, and Mrp4 and up-regulation of the basolateral Mrp3 transporter would reduce chemical secretion into urine. IntroductionPregnancy-induced hormonal and hemodynamic changes significantly alter renal function. In humans and rodents, increases in cardiac output and renal vasodilation enlarge the size of the kidneys, elevate renal plasma flow by 50-85%, and increase the rate of glomerular filtration by 40-65% (Chapman et al., 1998;Conrad, 2004;Maynard and Thadhani, 2009;Cornelis et al., 2011). Clinically, pregnant women exhibit proteinuria, glucosuria, and aminoaciduria, which have been attributed to alterations in renal function (Davison and Dunlop, 1980;Cornelis et al., 2011). Together, hyperfiltration and increased blood flow to the kidneys alter maternal pharmacokinetics by elevating the renal clearance of chemicals during pregnancy.Renal transporters are membrane-spanning proteins that play a critical role in facilitating the movement of toxins and drugs into the urine via secretion and into the blood via reabsorption. To enable these processes, transporters are prominently localized on both the apical (brush border) and basolateral membranes of proximal tubule epithelial cells. Transporters expressed within the kidneys are members of one of the two superfamilies: the solute carrier (SLC) and ATP-binding cassette (ABC) families. Efflux transporters that extrude chemicals from cells are members of both the ABC and the SLC families and include the multidrug resistance-associated proteins (Mrps), multidrug resistance proteins (Mdrs), breast cancer resistance protein (Bcrp), and multidrug and toxin extrusion proteins (Mates) (reviewed in Klaassen and Aleksunes, 2010).Recent studies have begun to explore transporter regulation in the kidneys during pregnancy and the subsequent postpartum period. In one study, expression of renal Mdr1b mRNA in mice decreased between mid and late gestation, with little to no change at the protein level (...

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Section: Discussionmentioning

confidence: 99%

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

2012

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“…As an example, glucose is transported by the facilitated GLUT transporters. It has also been proposed that metformin is transported from fetal to maternal circulations by facilitated diffusion [32].…”

Section: Transcellular Transfermentioning

confidence: 99%

Effects of Prenatal Cocaine Exposure on Human Pregnancy and Postpartum

Malek¹

2012

Pharm Anal Acta

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“…Kraemer et al (2006) provided the first direct evidence, using in vitro close-circle perfusions of a human placental cotyledon, that GLB is actively effluxed by a transporter other than P-gp. Shortly afterward, other studies suggested jpet.aspetjournals.org interaction of GLB with placental BCRP by use of specific inhibitors of a group of various transporters (Gedeon et al, 2006(Gedeon et al, , 2008Pollex et al, 2008;Zhou et al, 2008). In contrast to human studies, when tritium-labeled GLB was injected into pregnant rat, the fetal-to-maternal radioactivity ratio was 0.535, similar to diazepam (0.641) (Sivan et al, 1995).…”

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confidence: 99%

Transplacental Pharmacokinetics of Glyburide, Rhodamine 123, and BODIPY FL Prazosin: Effect of Drug Efflux Transporters and Lipid Solubility

Cygalova

Hofman²,

Čečková³

et al. 2009

J Pharmacol Exp Ther

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Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentrationdependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited.

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The Role of Placental Breast Cancer Resistance Protein in the Efflux of Glyburide across the Human Placenta

Cited by 90 publications

References 15 publications

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

Effects of Prenatal Cocaine Exposure on Human Pregnancy and Postpartum

Transplacental Pharmacokinetics of Glyburide, Rhodamine 123, and BODIPY FL Prazosin: Effect of Drug Efflux Transporters and Lipid Solubility

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