Received for publication February 17, 2005.
Revised April 21, 2005.
Accepted for publication April 25, 2005.

BETAMETHASONE PHARMACOKINETICS AFTER TWO PRODRUG FORMULATIONS IN SHEEP: IMPLICATIONS FOR ANTENATAL CORTICOSTEROID USE

Abstract

Objective. Maternal administration of betamethasone to enhance fetal lung maturation for women who threaten preterm labor is common clinical practice. However, recommendations regarding the choice of betamethasone formulations for perinatal use are vague. The disposition of betamethasone from two commonly used antenatal formulations is poorly understood. We therefore designed a study to capture the true pharmacokinetic profiles of betamethasone from these fast acting and dual release formulations. Methods. Betamethasone in sheep plasma was measured by a newly designed highly sensitive liquid chromatography tandem mass spectrometry assay after intramuscular injection (n = 4) of 0.25 mg/kg of betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Results. Betamethasone pharmacokinetics could be captured for 24 hours for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile appeared like a traditional Bateman function with a terminal half-life of 4 hours whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 hours. The latter is much longer than commonly reported and has been missed in the literature due to assay limitations. Extrapolations to humans indicate that although both formulations might have similar therapeutic indices, the dual formulation might be associated with a lower safety profile. Conclusion. In light of this newly identified long terminal half-life for the betamethasone dual formulation, dosing practices for betamethasone in pregnancy need to be reassessed.

Key words: drug absorption, fetal toxicology, half-life, metabolite kinetics, pharmacokinetic modeling, prodrugs, steroids, sustained release

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