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

摘要

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 [ 14C]GTx-024 derived radioactivity was observed. [14C]GTx- 024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5mL/h/kg) and mean elimination half-life of 0.6h and 16.4h 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 48h. Feces of intact rats contained primarily unchanged [ 14C]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 [14C]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.