Use of Primary Cultures of Rat Hepatocytes to Predict Toxicity in the Early Development of New Chemical Entities

Abstract

The new strategies for development of pharmacologically interesting compounds pose some limitations for standard toxicity assessment approaches due to: (1) increase in the number of compounds to be tested and (2) decrease in the amount of substance available for testing. In vitro methods are thus the only way to overcome such limitations. In this communication we present a cell-based model, using primary rat hepatocyte cultures, which we have validated using 23 compounds of the MEIC list as well as several Synthélabo proprietary products, covering a wide range of therapeutic indications. Our results show that our in vitro model gives a sufficient prediction for general toxicity by the oral route of administration (up to 2–4 weeks of treatment) in the rat to aid in decisions during early development. We also suggest that the comparative evaluation of the different parameters of cell toxicity examined may point to potential organ-related toxicity which could be further studied either with more complex in vitro or in vivo models. In conclusion, our results show that cell-based models for toxicity can be used for general screening purposes to predict in vivo toxicity in the early development of new chemical entities.