Study on Absorption, Distribution, Metabolism, and Excretion Properties of Novel Insecticidal GABA Receptor Antagonist, Pyraquinil, in Diamondback Moth Combining MALDI Mass Spectrometry Imaging and High-Resolution Mass Spectrometry

A thorough understanding of absorption, distribution, metabolism, and excretion (ADME) of insecticide candidates is essential in insecticide development and structural optimization. Here, ADME of pyraquinil, a novel insecticidal GABA receptorantagonist, inPlutella xylostellalarvae during the accumulation phase and depuration phase was investigated separately using acombination of UHPLC-Q-Orbitrap, HPLC-MS/MS, and MALDI-MSI. Five new metabolites of pyraquinil were identified, and ametabolic pathway was proposed. The oxidative metabolite (pyraquinil-sulfone) was identified as the main metabolite and confirmedby its standard. Quantitative results showed that pyraquinil was taken up by the larvae rapidly and then undergone a cytochromeP450s-mediated oxidative transformation into pyraquinil-sulfone.Both fecal excretion and oxidative metabolism were demonstratedto be predominant ways to eliminate pyraquinil inP. xylostellalarvae during accumulation, while oxidative metabolism followed byfecal excretion was probably the major pathway during depuration. MALDI-MSI revealed that pyraquinil was homogeneouslydistributed in the larvae, while pyraquinil-sulfone presented a continuous enrichment in the midgut during accumulation.Conversely, pyraquinil-sulfone located in hemolymph can be preferentially eliminated during depuration, suggesting its tissuetropism. It improves the understanding of the fate of pyraquinil inP. xylostellaand provides useful information for insecticidalmechanism elucidation and structural optimization of pyraquinil.

Automated summary

A comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of insecticide candidates is crucial for the development and optimization of insecticides. This study investigated the ADME of pyraquinil, a novel insecticidal GABA receptor antagonist, in Plutella xylostellalarvae using various analytical techniques. The results revealed the rapid uptake of pyraquinil by the larvae, followed by cytochrome P450-mediated oxidative transformation into pyraquinil-sulfone. Fecal excretion and oxidative metabolism were identified as the dominant mechanisms for pyraquinil elimination during accumulation, while oxidative metabolism followed by fecal excretion was likely the major pathway during depuration. The study also shed light on the tissue-specific distribution of pyraquinil and its main metabolite and provided valuable insights for the elucidation of insecticidal mechanisms and structural optimization of pyraquinil.