Establishment of Animal Models of Drug-induced Liver Injury and Analysis of Possible Mechanisms

Drug-induced liver injury (DILI) is one of leading causes of attrition during both early and late stages of drug development and postmarketing. DILI is generally classified into the intrinsic and idiosyncratic types. Intrinsic DILI is dose dependent and predictable as exemplified by acetaminophen toxicity. However, the occurrence of idiosyncratic DILI with very low incidence and severe liver damage is difficult to predict because of the complex nature of DILI and poor understanding of its mechanism. In this review, we summarize current knowledge and our accumulated experimental findings on the pathogenic mechanisms of DILI focusing on the reactive metabolites of drugs formed by drug-metabolizing enzymes and immune- and inflammation-related responses. Considering drug metabolism and pharmacokinetics, we have established nonclinical animal models of DILI for 10 types of clinical drug known to cause idiosyncratic DILI in humans. Using animal models, it has been shown that the formation of reactive metabolites and both innate and adaptive immunity are involved in the pathogenesis of drug hepatotoxicity. Based on information on biomarkers obtained from animal models, we developed a cell-based system that predicts the potential DILI risks of drugs. The results of these studies increased our understanding of the mechanisms of DILI and help to predict and prevent idiosyncratic DILI caused by drug candidates.