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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 21, 2005; DOI: 10.1124/jpet.105.095869

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Received for publication September 20, 2005.
Revised December 19, 2005.
Accepted for publication December 20, 2005.

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

Mahesh N. Samtani 1, Nancy A. Pyszczynski 1, Debra C. DuBois 1, Richard R. Almon 1, William J. Jusko 1*

1 State University of New York - Buffalo

* Address correspondence to: E-mail: wjjusko{at}acsu.buffalo.edu

Abstract

Our previous report describes the temporal steroid patterns during pharmacokinetic (PK) studies with dexamethasone (DEX) where doses of six 1 µmol/kg injections were given during gestational ages 18-20 days in rats. DEX PK was used in conjunction with the endogenous corticosterone profile to understand the regulation of fetal lung pharmacodynamics (PD). Expression of the glucocorticoid receptor (GR) and surfactant proteins A and B mRNA were chosen as lung maturational markers. GR appeared to be insensitive to the circulating glucocorticoids indicating that unlike the adult situation, GR was not under negative feedback control of its ligand. Surfactant protein B exhibited ~ 400-fold induction in control fetal lung during the last days of gestation and the inductive effect was even greater in the treatment group. Surfactant protein A displayed ~ 100-fold induction in control fetal lung during late gestation. However, the treatment group exhibited biphasic stimulatory and inhibitory effects for surfactant protein A. The inhibitory effect indicated that the chosen dosing scheme for DEX was not an optimal regimen. These data were used to determine by simulation the DEX regimen that would reproduce the temporal pattern of lung maturation observed in control animals. PK/PD modeling indicated that maintaining steroid exposure at approximately twice the equilibrium dissociation constant for the steroid/receptor interaction should produce optimal stimulation of both surfactant proteins. The simulations illustrate that administering smaller quantities of steroids over extended periods of time that produce sustained steroid exposure might be the optimal approach for designing dose-sparing antenatal corticosteroid therapy.


Key words: Dose-sparing Regimen, Fetal Lung Maturation, Glucocorticoid Receptor, Glucocorticoids, Pharmacodynamics, Surfactant Proteins


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M. N. Samtani, N. A. Pyszczynski, D. C. DuBois, R. R. Almon, and W. J. Jusko
Modeling Glucocorticoid-Mediated Fetal Lung Maturation: I. Temporal Patterns of Corticosteroids in Rat Pregnancy
J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 117 - 126.
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