Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs

Abstract

Unfavorable drug metabolism is the main reason for attrition of new chemical entities and withdrawal of drugs from the market, costing pharmaceutical companies a great deal of money and time. Therefore, obtaining information about the drug metabolism of a new chemical entity via the hepatic clearance in the early stages of the drug development process is crucial in guaranteeing its success. Human-based in vitro systems, especially liver microsomes, hepatocytes and liver slices are increasingly applied in the drug development process for this purpose. The aim is to determine which of these commonly used systems is the most appropriate for predicting hepatic clearance in humans. Although there is no “perfect” in vitro system, primary hepatocytes and the HepaRG cell line are the most representative systems of the liver at present. However, it has to be kept in mind that besides their potential to accurately predict in vivo clearance other influencing factors that may interfere with their ability to do so also have to be taken into consideration when deciding which is the most appropriate system.