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 7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects ( = 4) after a single 100-mg (100 Ci) 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-oxidation (M1, 50.3% in urine) and aza-adamantane -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-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.

Addressing Today’s Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of theSMN2mRNA Splicing Modifier Risdiplam

“…In a survey of enzymes involved in the metabolism of the FDA new drug applications between 2013 and 2016, FMO enzymes were listed as contributing to the metabolism of only 3 out of 98 cases (where data were available) and investigation with clinical DDI studies was not reported for any of these (Yu et al, 2018). FMOs are generally viewed favorably as contributing enzymes to the metabolism of drugs, recently reiterated in the case study for ABT-126 which is mainly metabolized by FMOs (Liu et al, 2018). FMO induction is not well-known and few drugs which inhibit FMOs have been identified, reducing the likelihood of DDIs (Cashman and Zhang, 2006).…”