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-mol kg Ϫ1 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.Endogenous glucocorticoids play a pivotal role in programming the development of the fetus and preparing it for life outside the womb (Liggins, 1994). During most of its gestational life, the fetus is exposed to very low levels of corticosteroids. A surge of corticosteroids in late pregnancy turns on fetal lung surfactant production that is necessary for lung maturation. Preterm birth occurs in about 10% of pregnancies where the neonate does not experience the late gestational steroid surge. These prematurely born infants experience respiratory distress syndrome (RDS) and require mechanical lung ventilation, which itself can cause additional lung diseases. RDS is a major cause of infant mortality and is among the most common and costly medical problems afflicting prematurely born infants (National Institutes of Health Consensus Panel, 1995).Synthetic fluorinated corticosteroids exhibit transplacental passage when administered to pregnant women because of low affinity for maternal corticosteroid binding globulin (CBG) and poor breakdown by placental steroid metabolizing enzymes (Pugeat et al., 1981;Diederich et al., 1998). DEX, in the form of its soluble phosphate ester prodrug, is administered prenatally to induce fetal lung maturation in women at risk of preterm delivery. This exogenous steroid administration has been shown to reduce the incidence of ...

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

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“…Therefore, it was assumed that the stress induced CST surge is not instantaneous and the time (21 min) to achieve the maximum CST (~600 ng/ml) was close to the first sampling time point of 15 min. Exogenous corticosteroids are known to inhibit endogenous CST secretion rapidly by a negative feedback loop on the HPA axis in humans as well as in rodents [43,47,48]. The IM MPL caused marked adrenal suppression indicated by CST at 12 h in the MPL group (50.3 ± 50.0 ng/ml) compared to the controls (292.1 ±78.2 ng/ml).…”

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review

“…Contrary to humans, the expression of surfactant in rats starts in the saccular phase on the 19th gestational day and is completed on the 21st-22nd day (at term) (86). The alveolar phase in rats does not begin until postpartum at postnatal days 4 -5 and slowly progresses throughout life (7,66,72) (Fig.…”

“…Antenatal corticosteroids protect to some degree against RDS when given to mothers with potential preterm labor from 24 -34 wk of gestation (86). The corticosteroids stimulate fetal lung maturation, including ATII cell differentiation and pul-monary surfactant synthesis (22a).…”

Modeling Glucocorticoid-Mediated Fetal Lung Maturation: II. Temporal Patterns of Gene Expression in Fetal Rat Lung

“…Understanding the system in a quantita-tive manner provides the unique benefit of using mathematical modeling to design optimal dosing regimens for antenatal corticosteroids. These models describe fetal lung maturation being initiated by the free plasma concentration of exogenous and endogenous steroids in fetal plasma (for detailed plasma glucocorticoid temporal patterns, see Samtani et al, 2006).…”