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.
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.
GTx, Inc. , Memphis, TN , USA and.
Juhyun
J
Kim
Ronghua
R
Wang
Karen A
KA
Veverka
James T
JT
Dalton
D000042:Absorption; D000284:Administration, Oral; D000577:Amides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine*; D000813:Anilides; D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D005243:Feces / Q000737:chemistry; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D011851:Radioactivity; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D013997:Time Factors; D014018:Tissue Distribution
D000577:Amides; D000813:Anilides; C547106:ostarine