Absorption, distribution, metabolism, excretion and metabolic transformation of Flonicamid in rats: Insights from radiotracing, metabolite profiling and multi-scale analysis.

Understanding flonicamid (FLO) disposition is important for interpreting its potential health implications. We investigated FLO metabolism in male Sprague-Dawley rats using 14C-radiotracing, high-resolution mass spectrometry, hepatic transcriptomics, density-functional-theory calculations, molecular docking, and molecular dynamics simulations. FLO was rapidly absorbed, widely distributed, and detected in the brain and testes. Parent FLO predominated in the radiochromatographic profiles, accounting for 70.3% of the total integrated radioactive peak area. TFNA-AM was the predominant metabolite, representing 72.3% of the total metabolite peak area. Its formation was consistent with cyanomethyl oxidative cleavage and computational predictions of molecular reactivity. Within 192 h, urinary recovery accounted for 84.1% of administered radioactivity, indicating predominantly urinary elimination. Integrated transcriptomic and molecular-simulation analyses further prioritized CYP2B2 as a candidate enzyme for subsequent biochemical evaluation of its potential role in the oxidative metabolism of FLO. FLO exposure was also associated with transcriptional changes in several hormone-related pathways in male rat liver. Collectively, these findings complement existing FLO studies by quantifying the recovery of FLO-derived material across excretion routes and the contributions of parent FLO and major metabolites to the recovered components. This information supports the interpretation of FLO disposition and the selection of analyses for subsequent exposure and toxicological studies.