Application of genetically modified rodent models in drug discovery and development for translation of clinical ADME properties

Abstract There has been much effort in striving to better understand the ambiguity in the translation of preclinical absorption, distribution, metabolism, and excretion (ADME) properties to the clinic. While various preclinical tools have been developed to address some of these scientific gaps, in vivo models are not commonly used to inform clinical ADME predictions due to species differences that may exist in the expression and/or activity of drug-metabolizing enzymes (DMEs) and drug transporters, as well as their regulation pathways. To bridge the disparity between animals and humans, genetically modified rodent models have been developed. This chapter provides an overview of various genetically modified models utilized in the study of DMEs and drug transporters, with a focus on knockout (KO), humanized, and human liver chimeric rodent models. The advantages and disadvantages with regard to their utility in the study of ADME will be discussed. Lastly, the current status and future perspectives of these models will be evaluated.