Karlsson Isabella B, Ekdahl Anja, Etchingham-Coll Hugh, Li Xue-Qing, Ericsson Cecilia, Ahlqvist Marie, Samuelsson Kristin
Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
Int J Mol Sci. 2025 Jan 28;26(3):1141. doi: 10.3390/ijms26031141.
Xenobiotics, including drugs, undergo metabolism to facilitate detoxification and excretion. Predicting a compound's metabolic fate before clinical trials is crucial for efficacy and safety. The existing methods rely on in vitro systems and in vivo animal testing. In vitro systems do not replicate the complexity of in vivo systems, and differences in biotransformation pathways between humans and nonclinical species may occur; thus, accurate predictions of human-specific drug metabolism are not always achieved. The aim of this study was to evaluate whether a chimeric mouse with a humanized liver, specifically the PXB-mouse, can mimic human metabolic profiles. PXB-mice have livers engrafted with up to 95% human hepatocytes. The biotransformation of 12 different small-molecule drugs were evaluated in PXB-mice (through analysis of blood and urine) and compared with the metabolism by hepatocytes from humans and mice and, when available, literature reports on human in vivo metabolism. The detected metabolites included major Phase I and II transitions, such as hydroxylation, and N- and O-dealkylation and glucuronidation. The metabolic patterns of the PXB-mice closely matched human in vivo data. It is also worth noting that the human hepatocytes formed most of the circulating metabolites, indicating that hepatocytes provide reliable predictions of human metabolic pathways. Thus, for drugs with human biotransformation pathways that are not observed in nonclinical species, the PXB-mouse model can be valuable in predicting human-specific metabolism.
包括药物在内的外源性物质会经历代谢过程以促进解毒和排泄。在临床试验前预测化合物的代谢命运对于疗效和安全性至关重要。现有方法依赖于体外系统和体内动物试验。体外系统无法复制体内系统的复杂性，并且人类和非临床物种之间的生物转化途径可能存在差异；因此，并非总能准确预测人类特有的药物代谢。本研究的目的是评估具有人源化肝脏的嵌合小鼠，特别是PXB小鼠，是否能够模拟人类代谢谱。PXB小鼠的肝脏移植了高达95%的人类肝细胞。通过对血液和尿液的分析，评估了12种不同小分子药物在PXB小鼠中的生物转化，并与人类和小鼠肝细胞的代谢以及（如有）关于人类体内代谢的文献报道进行了比较。检测到的代谢物包括主要的I相和II相转化，如羟基化、N-和O-脱烷基化以及葡萄糖醛酸化。PXB小鼠的代谢模式与人类体内数据密切匹配。还值得注意的是，人类肝细胞形成了大部分循环代谢物，这表明肝细胞能够可靠地预测人类代谢途径。因此，对于在非临床物种中未观察到人类生物转化途径的药物，PXB小鼠模型在预测人类特有的代谢方面可能具有重要价值。
