Cross-species metabolic characterization of eutylone and mechanism-based inhibition of CYP2D6 and CYP2B6 with drug interaction implications.
Abstract
Eutylone is a methylenedioxy-substituted synthetic cathinone increasingly detected in toxicological case analyses and commonly encountered under polydrug use conditions. To support metabolism-informed surveillance and risk assessment of emerging stimulants, this study comprehensively characterized eutylone disposition and interaction liability using plasma protein binding, metabolic stability in liver microsomes and hepatocytes across four species, untargeted feature-based molecular networking-based metabolite profiling, CYP phenotyping, and reversible and time-dependent inhibition assays. Eutylone exhibited moderate plasma protein binding (f<sub>u</sub> 0.38-0.51) and pronounced species differences in clearance, with high hepatic extraction in rat hepatocytes but only moderate extraction in human, mouse, and dog hepatocytes, indicating limited translatability of rodent data. Twenty metabolites were identified across phase I and phase II pathways, including O-demethylenation, N-deethylation, β-ketone reduction, hydroxylation, O-methylation, glucuronidation, and sulfation. While sixteen metabolites were conserved across species, four O-methylated and hydroxylated catechol metabolites were detected exclusively in rodents, and molecular networking revealed higher overall metabolite formation in rat hepatocytes. CYP2D6 was the primary enzyme mediating eutylone O-demethylenation, with secondary contributions from CYP2C19 and CYP2B6. Notably, eutylone caused time-dependent inhibition of CYP2D6 with K<sub>i</sub> = 4.2 µM and k<sub>inact</sub> = 0.069 min<sup>-1</sup>, and of CYP2B6 with K<sub>i</sub> = 32.9 µM and k<sub>inact</sub> = 0.080 min<sup>-1</sup>, without any measurable inhibition of UGT enzymes. This mechanism-based inhibition, comparable in efficiency to that reported for MDMA, suggests a clinically relevant potential to increase exposure to co-used CYP2D6 and CYP2B6 substrates. Together, these findings provide a translationally relevant metabolic framework for eutylone, highlight critical rat-human differences, and identify interaction-driven risks that are particularly relative in the current landscape of polydrug misuse.
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