Raymond Klairynne G, Taub Mitchell E, Wölke Stefan, Otto Sebastian, Chan Tom S
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut.
Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
Drug Metab Dispos. 2025 May 8;53(7):100093. doi: 10.1016/j.dmd.2025.100093.
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.
依克立普汀是一种有前景的候选药物，正被开发用于治疗与精神分裂症相关的认知障碍。有趣的是，在肝细胞或肝亚细胞组分中孵育后，未观察到人体内主要的主要代谢产物BI 761036（M232）。随后的研究表明，导致M232形成的代谢途径涉及2个连续的氧化步骤。首先，依克立普汀经CYP3A介导的氧化形成不稳定的甲醇亚胺（M526），随后经血浆介导的亚胺水解释放出M232和一种次要代谢产物M312。通过将M526与丁酰胆碱酯酶、对氧磷酶和人血清白蛋白（HSA）的选择性抑制剂在血浆中孵育，并在存在纯化或重组酯酶的情况下监测M526的水解，确定了负责M526水解的假定血浆亚胺酶。M526在血浆中仅被HSA水解形成M232，首次证明HSA介导的亚胺水解有助于形成一种主要的人体药物代谢产物。在发生样品重新分析的背景下，还研究了HSA介导的M526水解对单剂量依克立普汀（25 mg）给药个体采集的血浆样品中M232血浆浓度稳定性的潜在影响。这些发现突出了HSA在依克立普汀主要代谢产物生成中出人意料的代谢作用。意义声明：人血清白蛋白专门水解依克立普汀的中间代谢产物M526，导致形成依克立普汀的主要代谢产物M232。这一发现标志着人血清白蛋白直接参与主要人体药物代谢产物形成的首个证据，强调了人血清白蛋白重要且此前未被认识的代谢作用。
