Toxicokinetics, in vivo metabolic profiling and tissue distribution of chlorfenapyr in mice

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Abstract
Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by Streptomyces spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (t1/2), area under the curve (AUC) and peak concentration (Cmax) values of tralopyril were significantly higher than those of chlorfenapyr (P < 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood–brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC–MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning.
Funding Information
  • the Science and Technology Project of Xinjiang Production and Construction Corps (2022AB020)
  • Sichuan Provincial Science and Technology Support Program (2023YFS0184)
  • Chengdu Technology Support Program (2022-YF09-00021-SN)
  • the Fundamental Research Funds for the Central Universities (2023SCU12085)
  • The National Natural Science Foundation of China (82174077)
  • the Natural Science Foundation of Sichuan Province (2022NSFSC1292)
  • Chongqing Key Laboratory of Emergency Medicine open project (2023KFKT05)

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