ABSTRACT
Organ toxicities or dose-limiting toxicities, identified in nonclinical animal toxicology studies, can be addressed with mechanistic translational models. To increase throughput, models have been miniaturized like spheroids, or built to address questions not yet addressed like organoids for the pancreas or brain, or 3D tissue-engineered models to mimic flow. For both models, the ADME proteins were downregulated; however, the 3D spheroids typically had higher metabolic activity toward probe substrates. A goal is to have continual long-term testing of chronic organ responses to drugs via biomonitoring sensors, as well as PK-PD and ADME changes with exposure time. Untreated human liver slices and human kidney slices were evaluated with the U133A human array to assess gene expression changes under extended culture conditions. Metabolite profiling is achieved to different extents in liver microsomes, primary hepatocytes, and liver slices to compare the profiles of the toxicology species to humans.
