Dai Wanying, Piquette-Miller Micheline
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
Pharmaceutics. 2024 Jun 30;16(7):884. doi: 10.3390/pharmaceutics16070884.
Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation on maternal and fetal drug exposure has not been investigated. Using the PE rat model, we performed a pharmacokinetic study with rosuvastatin (RSV), a BCRP substrate, to investigate this impact. PE was induced in rats during gestational days (GD) 13 to 16 with daily low-dose endotoxin. On GD18, RSV (3 mg/kg) was administrated intravenously, and rats were sacrificed at time intervals between 0.5 and 6 h. As compared to controls, placental expression of Bcrp and Oatp2b1 significantly decreased in PE rats. A corresponding increase in RSV levels was seen in fetal tissues and amniotic fluid of the PE group ( < 0.05), while maternal plasma concentrations remained unchanged from the controls. An increase in Bcrp expression and decreased RSV concentration were seen in the livers of PE dams. This suggests that PE-mediated transporter dysregulation leads to significant changes in the maternal and fetal RSV disposition. Overall, our findings demonstrate that altered placental expression of transporters in PE can increase fetal accumulation of their substrates.
乳腺癌耐药蛋白（BCRP/ABCG2）转运体在子痫前期（PE）女性的胎盘以及PE的免疫大鼠模型中的表达下调。虽然许多药物是这种重要外排转运体的底物，但PE相关的BCRP下调对母体和胎儿药物暴露的影响尚未得到研究。我们使用PE大鼠模型，对BCRP底物瑞舒伐他汀（RSV）进行了药代动力学研究，以探讨这种影响。在妊娠第13至16天，每天给大鼠注射低剂量内毒素以诱导PE。在妊娠第18天，静脉注射RSV（3mg/kg），并在0.5至6小时的时间间隔处死大鼠。与对照组相比，PE大鼠胎盘Bcrp和Oatp2b1的表达显著降低。PE组胎儿组织和羊水中RSV水平相应升高（<0.05），而母体血浆浓度与对照组相比保持不变。PE母鼠肝脏中Bcrp表达增加，RSV浓度降低。这表明PE介导的转运体失调导致母体和胎儿RSV处置发生显著变化。总体而言，我们的研究结果表明，PE中转运体胎盘表达的改变可增加其底物在胎儿体内的蓄积。
