Effect of endotoxin on the expression of placental drug transporters and glyburide disposition in pregnant rats.
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.
Petrovic
Vanja
V
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
Wang
Jing-Hung
JH
Piquette-Miller
Micheline
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D005905:Glyburide / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D000089762:Multidrug Resistance-Associated Protein 2; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D004731:Endotoxins; D007004:Hypoglycemic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D005905:Glyburide