Dmd053983 603..610

Preventing and treating malaria in pregnancy is a global health priority. However little is known regarding the impact of malaria infection on the maternal and fetal disposition of pharmaceuticals and other xenobiotics. Our objective was to characterize expression of key determinants of drug-disposition in maternal and fetal tissues in a validated murine model of experimental placental malaria. Balb/c mice were infected with Plasmodium berghei at mid gestation [gestational day (GD) 13] and maternal, placental, and fetal tissues were collected at GD19. Expression of key ABC drug transporters and Cyp3a11 was examined by quantitative polymerase chain reaction. Western blotting was used to examine the protein expression of multidrug resistance protein 1 (MDR1, ABCB1). Compared with controls, placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the malaria-infected group (P < 0.05), as was placental MDR1 protein (P < 0.05). Significantly decreased hepatic expression of Abcc2, Abcg2, and Abcb11 and significantly increased expression of Abcb1b, Abcc1, and Abcc3 were seen in malaria-infected dams (P < 0.05) in comparison with uninfected controls. The expression of Abcb1a and Abcg2 was significantly decreased in fetal liver of infected dams, whereas levels of Abcb1b were increased (P < 0.05). Maternal and fetal hepatic expression of Cyp3a11 was significantly downregulated in the malaria group (P < 0.05). Together, malaria-induced alterations in the expression of transporters and drug-metabolizing enzymes in maternal and fetal tissues may alter the disposition of endogenous and therapeutic substrates, potentially impacting maternal and