Early prediction of potential hepatotoxic metabolites to aid lead selection in drug discovery
Abstract
Introduction Drug-induced liver injury is the leading cause of failure in clinical trials; therefore, additional toxicological tests are required at the outset of drug discovery. Materials and methods In this study, we propose the application of drug in vitro testing under metabolizing and non-metabolizing conditions, using HepaRG cells, expressing high metabolic capabilities, and HepG2 cells, with limited metabolic capacity, for hepatotoxicity detection and identification of potentially toxic metabolites. Results We tested 21 drugs approved for hepatotoxicity. The LC50 values of astemizole, clozapine, nitrofurantoin, and fusidic acid in HepG2 were approximately half of LC50s found in HepaRG; therefore, toxicity was attributed to the parent drug. Conversely, the LC50 of acetaminophen, doxorubicin, and moxifloxacin in HepG2 was approximately double that of HepaRG, indicating that toxicity was mainly elicited by hepatotoxic metabolites. Finally, the toxicity of ketoconazole, sulbactam, clindamycin, and nefazodone was associated with both the parent compounds and their metabolites. LC50 values were comparable. Furthermore, to identify toxic metabolites, the drug nefazodone and its main known metabolites, hydroxynefazodone (NFZ-OH) and triazoledione (NFZ-TD), were tested. This study showed that besides the parent drug nefazodone (LC50=19.9 µM), NFZ-OH (LC50=32.3 µM) is also responsible for hepatotoxicity while NFZ-TD (LC50>200 µM) is harmless. Conclusions The application of the…
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