Modeling Glucocorticoid-Mediated Fetal Lung Maturation: I. Temporal Patterns of Corticosteroids in Rat Pregnancy

Abstract

Preterm birth produces neonatal respiratory distress syndrome, and dexamethasone (DEX) is administered maternally to induce fetal lung maturation in women at risk of preterm delivery. Antenatal DEX therapy is largely empirical, and administering multiple doses of DEX produces undesirable metabolic and developmental effects in the fetus. It is hypothesized that pharmacokinetic/pharmacodynamic (PK/PD) assessment of the maternal/fetal disposition and selected effects of corticosteroids will allow insight into optimal dosing methods. An optimal regimen was defined as a dosing schedule that would reproduce the endogenous prenatal steroid exposure and up-regulation of fetal lung maturational markers precociously. This report focuses on designing such a regimen from a PK standpoint in rats. The temporal profile of endogenous corticosterone in control rats was captured using a radioimmunoassay and showed that maternal and fetal corticosterone increased significantly during the last days of gestation. Six 1-mumol kg(-1) intramuscular DEX doses separated by 12-h intervals were administered maternally starting at gestational age 18, and PK was captured using a liquid chromatography-mass spectrometry assay. Unbound DEX exhibited a fetal to maternal concentration ratio of 0.55, had a free fraction of 0.2 in maternal and 0.4 in fetal plasma, and declined with a half-life of approximately 3 h. DEX PK and plasma protein binding were linear during the study, and DEX exposure caused severe adrenosuppression. These temporal steroid profiles in the fetal circulation will be used to drive the PD effects reported in a companion paper and an optimal steroid regimen will be proposed.