title: Betamethasone pharmacokinetics after two prodrug formulations in sheep: implications for antenatal corticosteroid use.
abstract: 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. 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 betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Betamethasone pharmacokinetics could be captured for 24 h for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile had the appearance of a traditional Bateman function with a terminal half-life of 4 h, whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 h. The latter is much longer than is 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. 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 565 Hochstetter Hall, Buffalo, NY 14260, USA.
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.forename: Matthias
authors.initials: M
authors.lastname: Lohle
authors.forename: Angela
authors.initials: A
authors.lastname: Grant
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nathanielsz
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D011247:Pregnancy / Q000378:metabolism*; D011295:Prenatal Care; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012756:Sheep
chemical_list: D000305:Adrenal Cortex Hormones; D003692:Delayed-Action Preparations; D011355:Prodrugs; C018230:betamethasone acetate phosphate; C028994:betamethasone sodium phosphate; D001623:Betamethasone