EVALUATION OF ALTERNATIVE IN VIVO AND IN VITRO MODELS FOR DRUG METABOLISM TESTING IN DRUG DISCOVERY

Abstract

Alternative models which can overcome the limitations seen with primary human hepatocytes (PHH), that is limited availability, high cost and donor-to-donor variability, are constantly explored for drug metabolism testing in drug discovery. This thesis aimed to evaluate the drug metabolism profiles of alternative in vivo model, zebrafish, and in vitro model, hepatocyte-like cells (HLCs) derived from human fetal liver multipotent progenitor cells (hFLMPC) and human amniotic epithelial cells (hAEC), and compare them with current gold standard or common models used. Zebrafish possessed Cyp3a activity which could be induced and inhibited with a good degree of concordance to human. HLC (hFLMPC) expressed comparable levels of Phase II and drug transporter genes to PHH and the inter-individual profiles were relatively homogenous, which is promising for screening applications. Many genes were undetected in HLC (hAEC). The evaluation performed showed that both models are promising for use in drug discovery.