Investigation of Biotransformation Pathways in a Chimeric Mouse with a Humanized Liver

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.

PXB-mouse®; biotransformation; drug metabolism; hepatocytes; in vitro; in vivo.