Raymond_2025_Drug.Metab.Dispos_53_100093

Iclepertin was a promising drug candidate being developed for the treatment of cognitive impairment associated with schizophrenia. Interestingly, the predominant major metabolite in vivo in humans, BI 761036 (M232), was not observed after incubations in hepatocytes or hepatic subcellular fractions. Subsequent studies revealed that the metabolic pathway leading to the formation of M232 involves 2 sequential oxidation steps. First, iclepertin undergoes CYP3A-mediated oxidation to form the unstable carbinolimide (M526), followed by plasma-mediated imide hydrolysis to release M232 and a minor metabolite, M312. The putative plasma imidase responsible for the hydrolysis of M526 was identified by incubating M526 in plasma with selective inhibitors of butyrylcholinesterase, paraoxonase, and human serum albumin (HSA) and by monitoring the hydrolysis of M526 in the presence of purified or recombinant esterases. M526 was exclusively hydrolyzed by HSA in plasma to form M232, demonstrating for the first time that imide hydrolysis by HSA contributes to the formation of a major human drug metabolite. The potential impact of HSA-mediated hydrolysis of M526 on the stability of M232 plasma concentrations in plasma samples collected from individuals administered a single dose of iclepertin (25 mg) was also investigated in the context of incurred sample reanalysis. These findings highlight the unexpected metabolic role of HSA in the generation of a major metabolite of iclepertin. SIGNIFICANCE STATEMENT: Human serum albumin exclusively hydrolyzed the intermediate metabolite of iclepertin, M526, leading to the formation of M232, a major metabolite of iclepertin. This discovery marks the first evidence of human serum albumin's direct involvement in the formation of a major human drug metabolite, underscoring the significant and previously unrecognized metabolic role of human serum albumin.