Abstract
Mass balance, metabolism and excretion of ABT-126, an α7 nAChRs agonist, were characterized in healthy male subjects (n=4) following 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 primarily eliminated by hepatic metabolism followed by urinary excretion. Enzymatic studies suggested M1 formation is primarily mediated by human liver FMO3 and to a lesser extent by human kidney FMO1; M11 is mainly generated by human UGT1A4 while UGT2B10 plays a minor role mediating ABT-126 glucuronidation. Species dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not observed in rat and dog hepatocytes. This data suggest that monkey may be a more appropriate species for predicting human biotransformation and clearance. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacological activities. In summary, this study characterized ABT-126 metabolites in circulation and excreta and the primary elimination pathways of ABT-126 in human.
- enzyme kinetics
- flavin-containing monooxygenase/FMO
- glucuronidation/UDP-glucuronyltransferases/UGT
- liver/hepatic
- mass spectrometry/MS
- metabolite disposition
- metabolite identification
- The American Society for Pharmacology and Experimental Therapeutics