TY - JOUR T1 - Excretion, Mass Balance, and Metabolism of [<sup>14</sup>C]LY3202626 in Humans: An Interplay of Microbial Reduction, Reabsorption, and Aldehyde Oxidase Oxidation That Leads to an Extended Excretion Profile JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 698 LP - 707 DO - 10.1124/dmd.120.000009 VL - 48 IS - 8 AU - Kishore Katyayan AU - Ping Yi AU - Scott Monk AU - Kenneth Cassidy Y1 - 2020/08/01 UR - http://dmd.aspetjournals.org/content/48/8/698.abstract N2 - The mass balance, excretion, and metabolism of LY3202626 were determined in healthy subjects after oral administration of a single dose of 10 mg of (approximately 100 μCi) [14C]LY3202626. Excretion of radioactivity was slow and incomplete, with approximately 75% of the dose recovered after 504 hours of sample collection. The mean total recovery of the radioactive dose was 31% and 44% in the feces and urine, respectively. Because of low plasma total radioactivity, plasma metabolite profiling was conducted by accelerator mass spectrometry. 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 and 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 that M16 is oxidized in the liver by aldehyde oxidase 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.SIGNIFICANCE STATEMENT The excretion of radioactivity in humans after oral administration of a single dose of 10 mg of [14C]LY3202626 was very slow. The results from in vitro experiments suggested that an interplay between microbial reduction, reabsorption, and aldehyde oxidase oxidation (M2 → M16 → M2) could be a reason for extended radioactivity excretion profile. In vitro metabolism also showed that LY3202626 has the potential to form a reactive sulfenic acid intermediate that could potentially covalently bind to plasma protein and result in the observed unextractable radioactivity from plasma. ER -