Drug-Induced Liver Injury (DILI) is one of the major causes of attrition in clinical trials and drug withdrawal after marketing. Thus, it is considered important for pharmaceutical companies to predict hepatotoxicity early in non-clinical studies. On the other hand, many hepatotoxic compounds are idiosyncratic as well as intrinsic, which complicates prediction of DILI in nonclinical studies. In recent years, it has been reported that compounds which show both high lipophilicity and high daily dose are associated with a risk of hepatotoxicity (Rule of Two), and that multiple disorders of liver functions, such as dual inhibition of both BSEP and mitochondrial respiration, increase the risk of hepatotoxicity.

This study has aimed to extract features related to hepatotoxicity and help selecting candidate compounds by clarifying the profiles of the current physicochemical and in vitro evaluation systems (lipophilicity, daily dose, BSEP inhibition, mitochondrial respiratory inhibition, reactive metabolites) for 11 proprietary compounds that induced the elevation of blood liver enzymes in the clinical trials.

Among the 11 compounds, 8 compounds showed either high lipophilicity or high daily dose (daily dose > 100 mg), but none met both. Although the rule of two was not applied to these compounds, it was suggested that each parameter was involved in hepatotoxicity. On the other hand, 2 compounds each showed either dual inhibition of mitochondrial function and BSEP, or inhibition of mitochondrial function and production of reactive metabolites, and 1 compound showed inhibition of BSEP and production of reactive metabolites, suggesting that multiple disorders of in vitro parameters are related to hepatotoxicity. These results support recent literature and are useful for future prediction of clinical hepatotoxicity.