Association between drug-induced heart failure and CYP1A1, CYP1B1, and CYP3A4 inhibition: Utility of cytochrome P450 inhibition assay for evaluating cardiotoxicity of drug candidates.

Unpredictable adverse drug reactions (ADRs) present a significant challenge in drug development and require advanced prediction systems for ADRs. Previously, we identified a connection between drug-induced liver injury (DILI) and the inhibition of CYP1A1 or CYP1B1, reporting the usefulness of this inhibition data from these cytochrome P450s (P450s) for predicting DILI. This study aimed to investigate the utility of P450 inhibition data in predicting drug-induced organ toxicities beyond DILI. We selected 364 drugs with ADR information as test drugs from the public database SIDER (Side Effect Resource). Our focus was on 10 groups of ADRs affecting the liver, kidney, heart, blood/hematopoietic system, intestines, muscle, and lungs, as classified by MedDRA. The inhibitory activities of 10 human P450s were evaluated in vitro using recombinant enzymes and luminescent substrates. Our analyses revealed notable associations between heart failure and the inhibition of CYP1A1, CYP1B1, and CYP3A4. Heart failure-positive drugs tended to exhibit strong inhibition of these P450s compared to heart failure-negative drugs. Furthermore, most drugs that inhibited two or three of the three P450 forms were found to be heart failure-positive. These results suggest that the inhibition assay data for CYP1A1, CYP1B1, and CYP3A4 help assess drug-induced cardiotoxicity during drug development.