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

Analytical Chemistry and Pharmaceutics Group, RTI International, Research Triangle Park, North Carolina (J.P.B., J.S.G., J.M.H., Q.Z., B.F.T.); Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (I.M.K.); Toxicology Research Laboratory, University of Illinois at Chicago, Chicago, Illinois (M.L., A.L.); and Temple University School of Medicine, Philadelphia, Pennsylvania (A.S.)

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 4-hydroxy-16-fluoro-5-androsten-17β-ol and X( or β)-4-dihydroxy-16-fluoro-5-androsten-17β-ol. The identification of the monoglucuronide conjugate of 4-hydroxy-16-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 (16-fluoro-5-androsten-17β-ol and 16-fluoro-5-androsten-17-ol) and 4-hydroxy-16-fluoro-5-androsten-17β-ol that was present in urine in glucuronide form.