Assessment of drug-induced liver injury (DILI) risk of two novel pharmaceuticals based on in vitro covalent binding to human liver protein measurements and reactive metabolite trapping

ISSX-DMDG 2023 -- Idiosyncratic drug-induced liver injury (DILI) is a major cause of safety-related drug withdrawal post-market for small molecule medications and a major cause of attrition during drug development. Prediction of DILI remains difficult, and the underlying mechanisms are not fully understood. However, many drugs causing DILI are considered to form reactive metabolites and covalently bind to cellular macromolecules in the liver. In these studies, the potential covalent binding of two 14C-labelled novel pharmaceuticals (denoted Compound X and Compound Y) to human liver proteins and the formation of potential 'trapped' electrophilic metabolites of 14C-labelled Compound X [GSH-adducts] was investigated using human liver microsomes as the in vitro test model. Covalent binding of drug-related material was measured by liquid scintillation counting and trapped reactive metabolites were detected using high-resolution, accurate mass, mass spectrometry. The results were compared with three positive controls and one negative control. The results showed the covalent binding of Compound X and Compound Y and metabolites thereof to be low relative to the controls, and no GSH-adducts (representing reactive metabolites) were detected.