Use of primary cultures of rat hepatocytes to predict toxicity in the early development of new chemical entities

The new strategies for development of pharmacologically interesting compoun ds 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 th e only way to overcome such limitations. In this communication we present a cell-based model, using primary rat hepatocyte cultures, which we have val idated using 23 compounds of the MEIC list as well as several Synthelabo pr oprietary products, covering a wide range of therapeutic indications. Our r esults show that our in vitro model gives a sufficient prediction for gener al toxicity by the oral route of administration (up to 2-4 weeks of treatme nt) in the rat to aid in decisions during early development. We also sugges t that the comparative evaluation of the different parameters of cell toxic ity examined may point to potential organ-related toxicity which could be f urther studied either with more complex in vitro or in vivo models. In conc lusion, our results show that cell-based models for toxicity can be used fo r general screening purposes to predict in vivo toxicity in the early devel opment of new chemical entities. (C) 1999 Elsevier Science Ltd. All rights reserved.