Possibilities of predictive toxicology in assessing the potential hepatotoxicity of medicinal substances

Abstract

Currently, one of the "gold" standards for determining the potential toxicity of drugs is highly informative preventive screening (HCS). This method has become a powerful tool for the evaluation of molecular, cellular and tissue toxicity, especially in the field of predictive toxicology, aimed at predicting unwanted drug-related substances. It is critical for the pharmaceutical industry to identify and subsequently mitigate potential safety risks early in the R&D process and thus reduce toxicity and the safety-related shrinkage of drug development programs. In this article, we review some of the most common used HCS assays for predictive toxicology in the pharmaceutical industry. PubMed, Elsevier Science (Scopus), and Clarivate Analytics (Web of Science) research databases were searched for original research to identify the hallmarks of the HCS methodology. Hepatotoxicity is one of the most common causes of safety and toxicity related downsizing of potential drugs in the pharmaceutical industry, as well as drug withdrawals. Hepatotoxic substances are associated with xenobiotics, drugs, substances of natural origin and chemical agents that constitute an important cause of hepatic action. A single classification based on the mechanisms of toxicity makes it possible to distinguish between intrinsic hepatotoxicity (preliminary and dose-dependent) and idiosyncratic hepatotoxicity (invisible, non-mediated immune and metabolic reactions). HCS analyzes are not intended to replace animal testing because they cannot capture the full complexity of an organism. However, they can reduce the amount of animal testing by early detection of hazards and complement animal testing. Through early identification of safety risks and optimization of chemistry series across relevant safety endpoints, HCS assays for predictive toxicology hold the promise of enhancing the successful selection of new drug candidates with satisfactory toxicological properties.