Chapter 9: In Vitro Approaches for Determining Liver-Specific Toxicity of New Drug Candidates

This chapter provides a detailed review of how to set up an in vitro toxicity screening model that provides liver-specific data. The chapter focuses on liver anatomy and physiology, highlighting the key functions that make the liver unique. These key biochemical processes must also be present in the in vitro model in order for the data obtained to provide information that can be used to predict in vivo liver toxicity. There is a detailed discussion on the primary cell types in the liver, the polarity of the liver, and the functional unit of the liver. Next, the importance of drug metabolism, metabolic stability, and bioactivation are discussed. In vitro methods for measuring these endpoints are provided. The importance of measuring multiple parameters in the in vitro model is introduced with special emphasis on glutathione homeostasis, mitochondrial function, inhibition of bile flow, and activation of signaling pathways that predict liver toxicity. The importance of selecting the optimal cell model is described along with suggested endpoints to measure. Emphasis is placed on species-specific differences, relating in vitro exposure concentrations to in vivo plasma concentrations or maximum therapeutic plasma concentrations and the importance of multiple parameters. Examples of how to interpret in vitro toxicity data are also outlined in this chapter. Finally, the chapter provides a suggested screening strategy with the cell types and endpoints that provide the most useful information.