Intrauterine growth restriction may reduce hepatic drug metabolism in the early neonatal period

Abstract

The effects of intrauterine growth restriction (IUGR) extend well into postnatal life. IUGR is associated with an increased risk of adverse health outcomes, which often leads to greater medication usage. Many medications require hepatic metabolism for activation or clearance, but hepatic function may be altered in IUGR fetuses. Using a sheep model of IUGR, we determined the impact of IUGR on hepatic drug metabolism and drug transporter expression, both important mediators of fetal drug exposure, in late gestation and in neonatal life. In the late gestation fetus, IUGR decreased the gene expression of uptake drug transporter OATPC and increased P-glycoprotein protein expression in the liver, but there was no change in the activity of the drug metabolising enzymes CYP3A4 or CYP2D6. In contrast, at 3 weeks of age, CYP3A4 activity was reduced in the livers of lambs born with low birth weight (LBW), indicating that LBW results in changes to drug metabolising capacity in neonatal life. Together, these results suggest that IUGR may reduce hepatic drug metabolism in fetal and neonatal life through different mechanisms.