Humanized Mouse Tox Model
Current animal models are often poorly predictive of ADMET in man, noted Mike Piper, Ph.D., senior business development manager at CXR Biosciences. “This is driven by profound interspecies differences in the expression levels and functions of proteins involved in ADMET.” It’s also a major reason for development failure in the pharmaceutical and chemical industries.
CXR and TaconicArtemis have developed transADMET mice panels in which key murine ADMET genes are knocked out and their human counterparts inserted. Dr. Piper discussed three such panels—Cytochrome P450, Nuclear Receptor, and Drug Transporter—each representing critical pathways in compound metabolism, disposition, and safety.
For example, Cytochrome P450-dependent monooxygenases are a group of enzymes that account for the Phase I metabolism of the majority of drugs. Together, CYP3A4 and CYP2D6 catalyze the metabolism of over 60% of drugs in clinical use, according to Dr. Piper who noted these enzymes have diverged significantly between species, both in their multiplicity and substrate specificity. This divergence can cause altered drug metabolism profiles between animals and humans, leading to differences in pharmacokinetics, efficacy, and toxicity.
“We have derived and sourced a series of humanized and knockout CYP3A4 and CYP2D6 mouse models,” said Dr. Piper. “Depending on your needs, we can offer transADMET models where CYP450 expression is under control of the human promoter, or models with gut- or liver-specific CYP3A4 expression.”
The situation is much the same for nuclear receptor panels. Nuclear hormone receptors play a major role in regulating the body’s response to chemical exposure. The Pregnane X receptor (PXR) and Constitutive androstane receptor (CAR) have the ability to bind a wide range of exogenous and endogenous ligands and to control the expression of genes highly relevant to compound metabolism such as the cytochrome P450s and drug transporters.
However, sequence variation in PXR and CAR between animals and humans results in differences in the ability of exogenous ligands to interact and activate these transcription factors. Experimental data obtained in traditional animal models or in vitro test systems, may therefore, not reflect the interactions that occur in man, noted Dr. Piper.