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Research ArticleArticle

CHARACTERIZATION OF THE IN VITRO METABOLISM OF SELECTIVE ANDROGEN RECEPTOR MODULATOR USING HUMAN, RAT, AND DOG LIVER ENZYME PREPARATIONS

Wenqing Gao, Zengru Wu, Casey E. Bohl, Jun Yang, Duane D. Miller and James T. Dalton
Drug Metabolism and Disposition February 2006, 34 (2) 243-253; DOI: https://doi.org/10.1124/dmd.105.007112
Wenqing Gao
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Zengru Wu
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Casey E. Bohl
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Jun Yang
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Duane D. Miller
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James T. Dalton
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Abstract

Compound S4 [S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide] is a novel nonsteroidal selective androgen receptor modulator that demonstrates tissue-selective androgenic and anabolic effects. The purpose of this in vitro study was to identify the phase I metabolites, potential species differences in metabolism, and the cytochromes P450 (P450s) involved in the phase I metabolism of S4 using 14C-S4, recombinant P450s, and other liver enzyme preparations from human, rat, and dog. The major phase I metabolism pathways of S4 in humans were identified as deacetylation of the B-ring acetamide group, hydrolysis of the amide bond, reduction of the A-ring nitro group, and oxidation of the aromatic rings, with deacetylation being the predominant pathway observed with most of the enzyme preparations tested. Among the major human P450 enzymes tested, CYP3A4 appeared to be one of the major phase I enzymes that could be responsible for the phase I metabolism of S4 [Km = 16.1 μM, Vmax = 1.6 pmol/(pmol · min)] in humans and mainly catalyzed the deacetylation, hydrolysis, and oxidation of S4. In humans, the cytosolic enzymes mainly catalyzed the hydrolysis reaction, whereas the microsomal enzymes primarily catalyzed the deacetylation reactions. Similar phase I metabolic profiles were observed in rats and dogs as well, except that the amide bond hydrolysis seemed to occur more rapidly in rats. In summary, these results showed that the major phase I reaction of S4 in human, rat, and dog is acetamide group deacetylation.

Footnotes

  • These studies were supported by grants from GTx Inc. (Memphis, TN) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK59800) to J.T.D. and D.D.M. J.T.D. and D.D.M. are employees of GTx, Inc.

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

  • doi:10.1124/dmd.105.007112.

  • ABBREVIATIONS: SARM, selective androgen receptor modulator; AR, androgen receptor; S4, S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide; HPLC, high-performance liquid chromatography; P450, cytochrome P450; HLM, human liver microsome; ESI, electrospray ionization; MS, mass spectrometry; MS2, tandem mass spectrometry; DHT, dihydrotestosterone.

    • Received August 30, 2005.
    • Accepted November 2, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (2)
Drug Metabolism and Disposition
Vol. 34, Issue 2
1 Feb 2006
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Research ArticleArticle

CHARACTERIZATION OF THE IN VITRO METABOLISM OF SELECTIVE ANDROGEN RECEPTOR MODULATOR USING HUMAN, RAT, AND DOG LIVER ENZYME PREPARATIONS

Wenqing Gao, Zengru Wu, Casey E. Bohl, Jun Yang, Duane D. Miller and James T. Dalton
Drug Metabolism and Disposition February 1, 2006, 34 (2) 243-253; DOI: https://doi.org/10.1124/dmd.105.007112

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Research ArticleArticle

CHARACTERIZATION OF THE IN VITRO METABOLISM OF SELECTIVE ANDROGEN RECEPTOR MODULATOR USING HUMAN, RAT, AND DOG LIVER ENZYME PREPARATIONS

Wenqing Gao, Zengru Wu, Casey E. Bohl, Jun Yang, Duane D. Miller and James T. Dalton
Drug Metabolism and Disposition February 1, 2006, 34 (2) 243-253; DOI: https://doi.org/10.1124/dmd.105.007112
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