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Research ArticleArticle

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Vanja Petrovic, Jing-Hung Wang and Micheline Piquette-Miller
Drug Metabolism and Disposition September 2008, 36 (9) 1944-1950; DOI: https://doi.org/10.1124/dmd.107.019851
Vanja Petrovic
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Jing-Hung Wang
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Micheline Piquette-Miller
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Abstract

On average, 80% of pregnant women consume over-the-counter and/or prescription medications. The placenta is a crucial organ that can restrict fetal drug exposure. ATP-binding cassette (ABC) drug transporters play an important role in the placenta because they limit the transplacental transfer of xenobiotics. However, the impact of infection or inflammation on placental drug transporters is not well established. Thus, we examined the impact of endotox-in-induced inflammation on the placental expression of several key drug transporters in rats and its impact on fetal exposure to a drug substrate. Real-time polymerase chain reaction results demonstrated a significant time- and dose-dependent down-regulation of breast cancer resistance protein/Abcg2 mRNA in the placentas of endotoxin-treated rats with a corresponding decrease in protein levels. Likewise, the mRNA levels of several other ABC transporters (Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3) and members of the organic anion-transporting polypeptides (Slco1a4, Slco2b1, Slco4a1) were down-regulated. A biodistribution study was carried out with glyburide, a hypoglycemic sulfonylurea substrate of both ABC efflux and Oatp uptake transporters. Although administration of endotoxin resulted in comparable plasma concentrations of glyburide, a pronounced increase in the accumulation of glyburide was seen in the fetuses of endotoxin-treated rats (162% of controls, p < 0.01). Glyburide plasma protein binding was not affected by endotoxin treatment. Overall, our results demonstrated a significant reduction in the placental expression of several important drug transporters during endotoxin-induced inflammation. Alterations in glyburide distribution highlight the potential importance of both influx and efflux placental transporters in impacting fetal drug exposure.

Footnotes

  • This study was supported by an Operating Grant from the Canadian Institutes of Health Research.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.019851.

  • ABBREVIATIONS: ABC, ATP-binding cassette; Pgp, P-glycoprotein; Mdr, multidrug resistance; Mrp, multidrug resistance-associated protein; Bcrp, breast cancer resistance protein; Oatp, organic anion-transporting polypeptide; PCR, polymerase chain reaction; HPLC, high-performance liquid chromatography; TNF, tumor necrosis factor; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; ANOVA, analysis of variance.

    • Received November 23, 2007.
    • Accepted May 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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Research ArticleArticle

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Vanja Petrovic, Jing-Hung Wang and Micheline Piquette-Miller
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1944-1950; DOI: https://doi.org/10.1124/dmd.107.019851

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Research ArticleArticle

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Vanja Petrovic, Jing-Hung Wang and Micheline Piquette-Miller
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1944-1950; DOI: https://doi.org/10.1124/dmd.107.019851
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