Association of CYP1A1 and CYP1B1 inhibition in <i>in vitro</i> assays with drug-induced liver injury

Drug-induced liver injury (DILI) is one of the major causes for discontinuation drug development and withdrawal drugs from market. Since it known that reactive metabolite formation being substrates or inhibitors cytochrome P450s (P450s) are associated with DILI, we systematically investigated association between human P450 inhibition DILI. The inhibitory activity 266 DILI-positive (DILI drugs) 92 DILI-negative (no-DILI drugs), which were selected Liver Toxicity Knowledge Base (US Food Drug Administration), against 8 forms was assessed using recombinant enzymes luminescent substrates, threshold values showing highest balanced accuracy DILI discrimination determined each enzyme receiver operating characteristic analyses. results showed among tested, CYP1A1 CYP1B1 inhibited by more than no-DILI a statistical significance. We found 91% greater drugs. internal 5-fold cross-validation confirmed usefulness data threshold-based Although contribution these to metabolism in considered minimal, our present findings suggest assessment useful screening risk candidates at early stage development.