Absorption, distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats

Xenobiotica. 2013 Nov;43(11):993-1009. doi: 10.3109/00498254.2013.788233. Epub 2013 Apr 22.

Abstract

1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions. 2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [(14)C]GTx-024 derived radioactivity was observed. [(14)C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5 mL/h/kg) and mean elimination half-life of 0.6 h and 16.4 h in male and female rats, respectively. 3. Fecal excretion was the predominant route of elimination, with ∼70% of total radioactivity recovered in feces and 21-25% in urine within 48 h. Feces of intact rats contained primarily unchanged [(14)C]GTx-024 (49.3-64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8-12%) and the cyanophenol ring (M4, 1.3-1.5%), and glucuronidation of [(14)C]GTx-024 at the tertiary alcohol (M6, 3.5-3.7%). There was no quantifiable metabolite in plasma. 4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug.

MeSH terms

  • Absorption
  • Administration, Oral
  • Amides / chemistry
  • Amides / metabolism*
  • Amides / pharmacokinetics
  • Amides / urine*
  • Anilides
  • Animals
  • Autoradiography
  • Biotransformation
  • Feces / chemistry
  • Female
  • Male
  • Mass Spectrometry
  • Metabolomics
  • Radioactivity
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Reference Standards
  • Time Factors
  • Tissue Distribution

Substances

  • Amides
  • Anilides
  • ostarine