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Research ArticleArticle

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

Mahesh N. Samtani, Matthias Lohle, Angela Grant, Peter W. Nathanielsz and William J. Jusko
Drug Metabolism and Disposition August 2005, 33 (8) 1124-1130; DOI: https://doi.org/10.1124/dmd.105.004309
Mahesh N. Samtani
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Matthias Lohle
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Angela Grant
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Peter W. Nathanielsz
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William J. Jusko
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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.

Footnotes

  • This study was supported by Grants GM 24211 and HD 21350 from the National Institutes of Health and a predoctoral fellowship for M.N.S. from Merck. The liquid chromatograph/tandem mass spectrometer was obtained through a shared instrumentation grant (S10RR14573) from the National Center for Research Resources, National Institutes of Health.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.004309.

  • ABBREVIATIONS: LC/MS/MS, liquid chromatography/tandem mass spectrometry; QC, quality control; BMp, BMa, and BMp/a, betamethasone phosphate prodrug, acetate prodrug, and dual phosphate/acetate formulation-related variables; CBMp and CBMp/a, betamethasone concentrations; kaBMp and kaBMa, hybrid first-order rate constants; DoseBMp and DoseBMa, doses of prodrugs in terms of betamethasone equivalents; Vc/FBMp and Vc/FBMa, apparent volumes of distribution; FBMa and FBMp, bioavailability terms; FBMa/FBMp, relative bioavailability; Y(t), model output function; IC50,Free, free drug level causing 50% inhibition of cortisol synthesis rate.

    • Received February 16, 2005.
    • Accepted April 25, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (8)
Drug Metabolism and Disposition
Vol. 33, Issue 8
1 Aug 2005
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Research ArticleArticle

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

Mahesh N. Samtani, Matthias Lohle, Angela Grant, Peter W. Nathanielsz and William J. Jusko
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1124-1130; DOI: https://doi.org/10.1124/dmd.105.004309

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Research ArticleArticle

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

Mahesh N. Samtani, Matthias Lohle, Angela Grant, Peter W. Nathanielsz and William J. Jusko
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1124-1130; DOI: https://doi.org/10.1124/dmd.105.004309
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