TY - JOUR T1 - Excretion, Mass balance and Metabolism of [<sup>14</sup>C] LY3202626 in Humans: An interplay of microbial reduction, reabsorption, and AO oxidation that leads to an extended excretion profile JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000009 SP - DMD-AR-2020-000009 AU - Kishore Kumar Katyayan AU - Ping Yi AU - Scott A Monk AU - Kenneth C. Cassidy Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/06/04/dmd.120.000009.abstract N2 - The mass balance, excretion, and metabolism of LY3202626 were determined in healthy subjects following oral administration of a single dose of 10 mg (approximately 100 mCi) [14C] LY3202626. Excretion of radioactivity was slow and incomplete, with approximately 75% of the dose recovered after 504 h of sample collection. The mean total recovery of the radioactive dose was 31% and 44% in the feces and urine, respectively. Due to low plasma total radioactivity, plasma metabolite profiling was conducted by accelerator mass spectrometry (AMS). Metabolism of LY3202626 occurred primarily via O‑demethylation (M2) and amide hydrolysis (M1, M3, M4, and M5). Overall, parent drug, M1, M2, and M4 were the largest circulating components in plasma, and M2 and M4 were the predominant excretory metabolites. The slow elimination of total radioactivity was proposed to result from an unusual enterohepatic recirculation pathway, involving microbial reduction of metabolite M2 to M16 in the gut, reabsorption of M16, followed by hepatic oxidation of M16 back to M2. Supporting in vitro experiments showed that M2 is reduced to M16 anaerobically in fecal homogenate and M16 is oxidized in the liver by aldehyde oxidase (AO) to M2. LY3202626 also showed a potential to form a reactive sulfenic acid intermediate. A portion of plasma radioactivity was unextractable and presumably bound covalently to plasma proteins. In vitro incubation of LY3202626 in human liver microsomes in the presence of NADPH with dimedone as a trapping agent implicated the formation of the proposed sulfenic acid intermediate. ER -