P21-10 Evaluating CYP Interactions in Mixture Toxicity to form Common Kinetic Groups (CKGs)

Mixture assessments have conventionally been based on toxicodynamic principles, employing the dose addition concept and focusing on target organ toxicity and the mode of action. Although relatively effective, the dose addition concept does not account for dissimilar modes of action or interaction. Incorporating toxicokinetic interaction, we propose a refined strategy for mixture assessments. Braeuning et al. introduced the concept of Common Kinetic Groups (CKGs), that includes the consideration of ADME (Absorption, Distribution, Metabolism, and Excretion) properties and grouping chemicals based on their potential as inhibitors, substrates, or inducers of molecular mechanisms (i.e. enzymes) [1] . This study focuses on one of the most relevant CYP (Cytochrome P450) enzymes, CYP3A4, pivotal in xenobiotic metabolism, to investigate potential inhibitors and/or substrates within mixtures. We screened over 200 active substances using in silico to prioritise potential inhibitors and substrates, followed by in vitro validation of potential inhibitors. To test the applicability of the CKG concept, binary mixtures were analysed for dose addition effects. Furthermore, we identified a gap in predictive models for enzyme induction and addressed this gap by considering PXR-mediated induction predictions to expand the list of potential inducers. Integrating toxicokinetic principles into a mixture toxicity assessment not only enhances regulatory strategies for risk assessment and management but also facilitates informed decision-making in chemical safety. Furthermore, employing in silico and in vitro methods together improves the efficiency of screening efforts, potentially reducing reliance on traditional in vivo studies while ensuring reliable starting points.