Infection-Mediated Modulation of Drug Transporters in Pregnancy; Implications for Fetal Drug Exposure.

摘要

Inflammation-mediated changes in the expression and activity of ABC drug-efflux transporters have been shown to alter disposition of their substrates. While ABC transporters play an important role in placenta by limiting transplacental transfer of xenobiotics, little is known about the impact of inflammatory stimuli on these transporters during pregnancy.;Using animal models, we investigated the impact of infection-induced acute inflammation on the expression of P-GP (ABCB1), BCRP (ABCG2) and MRP1-3 (ABCC1-3) efflux transporters, as well as several OATP (SLCO) uptake transporters in livers and placentas of pregnant rats. We explored how changes in placental transporter levels impact fetal drug exposure.;Our studies demonstrated that endotoxin and polyinosinic/polycytidylic acid [poly(I:C)] induce pro-inflammatory cytokine levels in plasma of pregnant rats and generally downregulate mRNA and protein expression of several important hepatic and placental drug uptake and efflux transporters. Moreover, these changes were associated with alterations in maternal and fetal drug disposition of clinically relevant substrates. Downregulation of Bcrp was associated with a pronounced increase in fetal accumulation of its substrate, glyburide in endotoxin-treated rats. Significantly increased maternal exposure to P-gp substrate, lopinavir was observed in poly(I:C)-treated rats, with evidence of altered placental transfer and fetal disposition. Additionally, bile acids, which are endogenous substrates of many affected hepatic transporters, were significantly increased in maternal plasma of poly(I:C)-treated rats. While the observed differences could also be attributed to inflammation-induced variability in drug metabolism and protein binding, our findings provide evidence that decreased expression of efflux transporters significantly contributes to modulation of materno-fetal transport and disposition.;Lastly, translational studies utilizing human placenta demonstrated similar impact of infections on expression of drug transporters such as BCRP and OATP2B1, indicating the need for a closer clinical investigation of inflammation-mediated changes in transporter expression and the possible impact on maternal drug disposition and fetal drug exposure.