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Research ArticleArticle

Identification of [14C]Fluasterone Metabolites in Urine and Feces Collected from Dogs after Subcutaneous and Oral Administration of [14C]Fluasterone

Jason P. Burgess, Jonathan S. Green, Judith M. Hill, Qiao Zhan, Matthew Lindeblad, Alexander Lyubimov, Izet M. Kapetanovic, Arthur Schwartz and Brian F. Thomas
Drug Metabolism and Disposition May 2009, 37 (5) 1089-1097; DOI: https://doi.org/10.1124/dmd.108.023614
Jason P. Burgess
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Jonathan S. Green
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Judith M. Hill
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Qiao Zhan
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Matthew Lindeblad
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Alexander Lyubimov
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Izet M. Kapetanovic
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Arthur Schwartz
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Brian F. Thomas
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Abstract

The objective of this research was the identification of the metabolic profile of fluasterone, a synthetic derivative of dehydroepiandrosterone, in dogs treated orally or subcutaneously with [4-14C]fluasterone. Separation and characterization techniques used to identify the principal metabolites of fluasterone in urine and feces included high-performance liquid chromatography (HPLC), liquid scintillation spectrometry, HPLC/tandem mass spectrometry, and NMR. In urine, the majority of the radioactivity was present as two components that had apparent molecular weights consistent with their tentative identification as monoglucuronide conjugates of 4α-hydroxy-16α-fluoro-5-androsten-17β-ol and X(α or β)-4α-dihydroxy-16α-fluoro-5-androsten-17β-ol. The identification of the monoglucuronide conjugate of 4α-hydroxy-16α-fluoro-5-androsten-17β-ol was also supported by NMR data. In support of this identification, these metabolites were cleaved with glucuronidase enzyme treatment, which gave rise to components with molecular weights again consistent with the aglycones of a monohydroxylated, 17-keto reduced (dihydroxy) fluasterone metabolite and a dihydroxylated, 17-keto reduced (trihydroxy) fluasterone metabolite. In feces, nonconjugated material predominated. The primary metabolites eliminated in feces were the two hydroxy fluasterone metabolites arising from 17-reduction (16α-fluoro-5-androsten-17β-ol and 16α-fluoro-5-androsten-17α-ol) and 4α-hydroxy-16α-fluoro-5-androsten-17β-ol that was present in urine in glucuronide form.

Footnotes

  • This work was supported by the National Institutes of Health Division of Cancer Prevention and Control [Contract N01-CN-43306].

  • Parts of this work were previously presented as a poster as follows: Zhan Q, Hill JM, Chao A, Green JS, Luybimov A, Kapetanovic IM, and Thomas BF (2007) Characterization of the metabolites of [14C]fluasterone excreted in dog urine and feces using LC/MS/MS. American Association of Pharmaceutical Scientists 2007 Annual Meeting; 2007 Nov 10–16; San Diego, CA. American Association of Pharmaceutical Scientists, Arlington, VA.

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

  • doi:10.1124/dmd.108.023614.

  • ABBREVIATIONS: DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; LC/MS/MS, liquid chromatography/tandem mass spectrometry; LC/MS, liquid chromatography/mass spectrometry; 17β-OH fluasterone, 16α-fluoro-5-androsten-17β-ol; 17α-OH fluasterone, 16α-fluoro-5-androsten-17α-ol; HPLC/UV/LSS, high-performance liquid chromatography/UV/liquid scintillation spectrometry; LSS, liquid scintillation spectrometry; HPLC, high-performance liquid chromatography; HPLC/LSS, high-performance liquid chromatography/liquid scintillation spectrometry; HPLC/MS/MS, high-performance liquid chromatography/tandem mass spectrometry; 4α-17β-diOH fluasterone, 4α-hydroxy-16α-fluoro-5-androsten-17β-ol; X(α or β)-4α-17β-triOH fluasterone, X(α or β)-4α-dihydroxy-16α-fluoro-5-androsten-17β-ol; APCI, atmospheric pressure chemical ionization; G6PDH, glucose-6-phosphate dehydrogenase.

    • Received July 30, 2008.
    • Accepted January 29, 2009.
  • U.S. Government work not protected by U.S. copyright.
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Drug Metabolism and Disposition: 37 (5)
Drug Metabolism and Disposition
Vol. 37, Issue 5
1 May 2009
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Research ArticleArticle

Identification of [14C]Fluasterone Metabolites in Urine and Feces Collected from Dogs after Subcutaneous and Oral Administration of [14C]Fluasterone

Jason P. Burgess, Jonathan S. Green, Judith M. Hill, Qiao Zhan, Matthew Lindeblad, Alexander Lyubimov, Izet M. Kapetanovic, Arthur Schwartz and Brian F. Thomas
Drug Metabolism and Disposition May 1, 2009, 37 (5) 1089-1097; DOI: https://doi.org/10.1124/dmd.108.023614

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Research ArticleArticle

Identification of [14C]Fluasterone Metabolites in Urine and Feces Collected from Dogs after Subcutaneous and Oral Administration of [14C]Fluasterone

Jason P. Burgess, Jonathan S. Green, Judith M. Hill, Qiao Zhan, Matthew Lindeblad, Alexander Lyubimov, Izet M. Kapetanovic, Arthur Schwartz and Brian F. Thomas
Drug Metabolism and Disposition May 1, 2009, 37 (5) 1089-1097; DOI: https://doi.org/10.1124/dmd.108.023614
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