RT Journal Article
SR Electronic
T1 Disposition and Metabolism of LY2452473, a Selective Androgen Receptor Modulator, in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2354
OP 2364
DO 10.1124/dmd.112.047613
VO 40
IS 12
A1 Ping Yi
A1 Jessica Fayer Rehmel
A1 Kenneth Cassidy
A1 Chad Hadden
A1 Kristina Campanale
A1 Nita Patel
A1 Jason Johnson
YR 2012
UL http://dmd.aspetjournals.org/content/40/12/2354.abstract
AB The disposition and metabolism of isopropyl N-[(2S)-7-cyano-4-(2-pyridylmethyl)-2,3-dihydro-1H-cyclopenta[b]indol-2-yl]carbamate (LY2452473; a selective androgen receptor modulator) in humans was characterized after a single 15-mg (100 μCi) oral dose of [14C]LY2452473 to six healthy male subjects. LY2452473 was absorbed rapidly (time to reach maximum plasma concentration for both LY2452473 and total radioactivity was 2–3 h) and cleared slowly (plasma terminal t1/2 of 27 h for LY2452473 and 51 h for the total radioactivity). LY2452473 and metabolites S5 (acetylamine) and S12 (hydroxylation on the cyclopentene) were major circulating entities in plasma, accounting for approximately 42, 21, and 35% of the total radioactivity exposure, respectively, as calculated from relative area under the concentration versus time curves from zero to 48 h derived from the plasma radiochromatograms. The radioactive dose was almost completely recovered after 312 h with 47.9% of the dose eliminated in urine and 46.6% in feces. Minimal LY2452473 was detected in excreta, indicating that metabolic clearance was the main route of elimination. Multiple metabolic pathways were observed with no single metabolic pathway accounting for more than 30% of the dose in excreta. Metabolite S10 (a diol across the cyclopenta-indole linkage) was the largest excretory metabolite (approximately 14% of the dose). S10 displayed interesting chemical and chromatographic properties, undergoing conversion to the corresponding epoxide under acidic conditions and conversion back to the diol under neutral conditions. An in vitro phenotyping approach indicated that CYP3A4 was the largest contributor to LY2452473 depletion.