CULTURED-HEPATOCYTES AS INVESTIGATIONAL MODELS FOR HEPATIC TOXICITY -PRACTICAL APPLICATIONS IN DRUG DISCOVERY AND DEVELOPMENT

Drugs can fail at any phase during discovery, preclinical or clinical development due to unacceptable levels of toxicity, and liver is commo nly the principle target organ. Investigational toxicology methods, us ing appropriate models and hypotheses, can often resolve problems, ide ntify toxic chemical substituents and salvage therapeutic discovery pr ograms. While in vivo models are used to investigate hepatic drug effe cts in the context of toxicokinetics and systemic influences, cell cul ture models provide in vitro systems for investigating specific mechan isms in a precisely controlled environment. Using primary hepatocytes isolated from laboratory animals, we have explored several drug-induce d hepatic disorders that surfaced during different phases of drug disc overy and development. Additionally, the use of human hepatocytes has allowed us to address concerns for human exposure, examine human relev ance of animal data, and provide perspective on problems encountered i n clinical trials.