Limited fetal metabolism of rosiglitazone: Elimination via the maternal compartment in the pregnant ewe

Despite the fact that fetal drug exposure is common, the disposition of drugs in the fetus is poorly understood. This study aimed to investigate fetal placental and non-placental disposition of rosiglitazone in the pregnant ewe. Steady state was reached after day 5 of fetal infusion, and were ~1.8 fold higher than maternal concentrations (P < 0.001). The AUC for fetal rosiglitazone concentration throughout the infusion was inversely correlated with placental and fetal weight. Metabolic activity of the fetal liver microsomes were ~25 fold lower than maternal microsomes (P < 0.001). The findings suggest that trans-placental transfer is the major route through which rosiglitazone is cleared from the fetal compartment, while non-placental hepatic elimination makes only a minor contribution. This supports a limited capacity of the fetus for eliminating this class of drugs, and highlights the potential for drug toxicity when administering pharmacotherapy to the mother/fetus in human pregnancy.