Using Chimeric Mice with Humanized Livers to Predict Human Drug Metabolism and a Drug-Drug Interaction
News Nov 16, 2012
Inter-species differences in drug metabolism have made it difficult to use pre-clinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDI) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite prior to human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, since the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was co-administered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of pre-clinical drug assessment.
This article is published on line in The Journal of Pharmacology and Experimental Therapeutics and is free to access.
Chili Pepper Derived Anti-Obesity Drug Shows Promise in Animal TrialsNews
A novel drug based on capsaicin, the compound that gives chili peppers their spicy burn, caused long term weight loss and improved metabolic health in mice eating a high fat diet.READ MORE
Lab Innovations 2018 – Registration Opens and Keynotes AnnouncedNews
Learn and earn CPD points at the UK’s only lab-dedicated showcase and scientific seminar series.READ MORE