Dissertation

Advanced in vitro models for studying drug induced toxicity

Promotor: Prof.dr. B. van de Water, Co-promotor: L.S. Price

Author: S.C. Ramaiahgari
Date: 04 June 2014
Links: Thesis in Leiden Repository

Bringing safe medicines to the market has remained a major challenge to the pharmaceutical industry. Recent years have seen increased drug attrition rates due to toxicity - even after rigorous testing in both in vitro and in vivo test models. This is partly due to poor prediction of human-specific responses in these models. This thesis aims to address the issue by developing advanced in vitro models and methods that can complement and improve the predictive power of in vitro assays at preclinical level. Liver and kidneys are often susceptible to drug insult due to their respective roles in drug metabolism and reabsorption. We have developed a robust 3D in vitro model for liver toxicity studies, this model shows many hallmarks of in vivo hepatocytes, is applied in a 384-micro-well format and is compatible with standard medium- and high-throughput lab infrastructure for routine drug screening. This thesis also discusses the role of immune mediators in aggravating kidney toxicity and use of sophisticated high-content screening approach to measure apoptosis and necrosis in real time. These models are promising new tools for preclinical drug safety testing.