Humanized liver rodents are created by ablation of native hepatocytes through either chemical or genetic alterations that cause hepatocyte damage. Human hepatocytes are transplanted into these animals, they repopulate the host liver replacing the endogenous liver with human cells. This type of humanization must be done in an immunodeficient or “SCID” animals so that the transplanted human cells are not rejected. The resulting humanized liver chimeric animal is an excellent model for studying in-vivo liver toxicity, drug transport, drug-drug interactions (DDI) and metabolism, as well as PK/PD (pharmacokinetics/ pharmacodynamics).
The evaluation of drug metabolism in fully mature human hepatocytes is important because the liver is the key organ for metabolism of xenobiotics and many hepatic enzymes are species specific. However, one of the major roadblocks for testing new drug candidates is the limited availability of human hepatocytes and the inability of stem cell-derived hepatocytes to fully mature in vitro. Liver humanized models enable discovery and toxicity testing on human hepatocytes in-vivo and provides a potentially unlimited source of fully differentiated mature human hepatocytes. Due to increasingly diverse chemical structures, it has become important to screen drug candidates for not only cytochrome P450 induced toxicity, but also other drug metabolism enzymes and drug-drug interactions (DDI). One recent study demonstrated, humanized liver mice could have predicted liver toxicity and prevented a failed clinical trial that led to the death of 5 patients by an investigational hepatitis B drug known as fialuridine (FIAU).
Humanize liver rats provide several significant advantages over using mouse models. Recently, genetically modified rats have been created which are fully immunocompromised, similar to the NSG mouse, that eliminates the need for chemical immunosuppression which could interfere with ADME-Tox studies. Rats are the preferred model in pre-clinical drug studies because their larger size facilitates procedures otherwise difficult in mice, including studies using instrumentation, blood sampling, and surgeries. In rats, ten times the amount of tissue and serum can be collected per animal, enabling serial blood draws.