Received for publication November 27, 2007.
Revised May 13, 2008.
Accepted for publication May 21, 2008.

Effect of endotoxin on the expression of placental drug transporters and glyburide disposition in pregnant rats

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. ABC drug transporters play an important role in placenta, as they limit the transplacental transfer of xenobiotics. However, the impact of infection or inflammation on placental drug transporters is not well established. We thus examined the impact of endotoxin-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 PCR results demonstrated a significant time- and dose-dependent downregulation of Bcrp/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 (Mdr1a/Abcb1a, Mdr1b/Abcb1b, Mrp1-3/Abcc1-3) as well as members of the organic anion transporting polypeptides (Oatp1a4/Slco1a4, Oatp2b1/Slco2b1, Oatp4a1/Slco4a1) were downregulated. A biodistribution study was carried out with glyburide, a hypoglycemic sulfonylurea substrate of both ABC efflux and Oatp uptake transporters. While 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.

Key words: ABC transporters, cytokines, drug distribution, HPLC, organic anion transport, regulation of gene expression, transporters