Metabolism and Disposition of a Novel Selective α7 Neuronal Acetylcholine Receptor Agonist ABT-126 in Humans: Characterization of the Major Roles for Flavin-Containing Monooxygenases and UDP-Glucuronosyl Transferase 1A4 and 2B10 in Catalysis.

Abstract

Mass balance, metabolism, and excretion of ABT-126, an α7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects (n = 4) after a single 100-mg (100 μCi) oral dose. The total recovery of the administered radioactivity was 94.0% (±2.09%), with 81.5% (±10.2%) in urine and 12.4% (±9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized, with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces. The primary metabolic transformations of ABT-126 involved aza-adamantane N-oxidation (M1, 50.3% in urine) and aza-adamantane N-glucuronidation (M11, 19.9% in urine). M1 and M11 were also major circulating metabolites, accounting for 32.6% and 36.6% of the drug-related material in plasma, respectively. These results demonstrated that ABT-126 is eliminated primarily by hepatic metabolism, followed by urinary excretion. Enzymatic studies suggested that M1 formation is mediated primarily by human liver flavin-containing monooxygenase (FMO)3 and, to a lesser extent, by human kidney FMO1; M11 is generated mainly by human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4, whereas UGT 2B10 also contributes to ABT-126 glucuronidation. Species-dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not in rat and dog hepatocytes, suggesting that monkeys constitute an appropriate model for predicting the fate of compounds undergoing significant N-glucuronidation. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacologic activities. In summary, this study characterized ABT-126 metabolites in the circulation and excreta and the primary elimination pathways of ABT-126 in humans.