Humanised mice in drug metabolism studies
5 September 2018
Dr Anja Ekdahl, senior biotransformation scientist at Admescope, has contributed her drug metabolism expertise to a freshly published research paper, “The metabolic fate of fenclozic acid in chimeric mice with a humanized liver”, in collaboration with leading experts in the field of reactive drug metabolites, Lars Weidolf and Richard Thompson from AstraZeneca and professor Ian Wilson from Imperial College London. The work reports several glutathione-derived metabolites unique to the liver-humanised mice, pointing to possible formation of chemically reactive metabolites. Fenclozic acid, originally developed as an alternative to high dose Aspirin in the 1960s, had an excellent safety profile in the preclinical species but was withdrawn from development due to unexpected hepatotoxicity in the clinical trials. The mechanisms for the human-specific hepatotoxicity have so far remained elusive but the findings in this publication might provide an explanation.
According to the research team, the discovery of novel metabolites in liver-humanised mice opened new avenues in exploring the metabolism of fenclozic acid and further studies will follow. The authors also conclude that although the mouse model is promising for predicting human metabolism, a more thorough characterisation of the model is needed.
The results of this study provide more support that humanised animals could serve as valuable tools in drug metabolism studies, especially when traditional models fail to replicate the human response.
The article was published in Archives of Toxicology.
New team member
We are happy to welcome Annina Kelloniemi, a biochemist with a BSc in pharmacy, as a research scientist to our team! She will defend her doctoral thesis titled “Novel factors regulating cardiac remodeling in experimental models of cardiac hypertrophy and failure” in October.