Chloropyridinyl neonicotinoid insecticides: Diverse molecular substituents contribute to facile metabolism in mice

Chloropyridinyl neonicotinoid insecticides play a major role in crop protection and flea control on cats and dogs. Imidacloprid (IMI), nitenpyram (NIT), thiacloprid (THI), and acetamiprid (ACE) have in common the 6-chloro-3-pyridinylmethyl group but differ in the nitroguanidine, nitromethylene, or cyanoamidine substituent on an acyclic or cyclic moiety. Earlier metabolism studies were made with rats, goats, and hens but not with mice or under conditions suitable to compare metabolic pathways or pharmacokinetics. In this investigation, IMI, NIT, THI, and ACE were individually administered ip to mice at 10 or 20 mg/kg for analysis of brain, liver, and plasma at 15-240 min and 0-24 h urine by HPLC/DAD, LC/MSD, and LC/MS/MS. Maximum levels of the parent compounds in brain were 11-16 ppm (NIT and THI), 6 ppm (IMI), and 3 ppm (ACE). Persistence in the tissues was greater for ACE than the other neonicotinoids. Urinary excretion of the parent compound was greatest with NIT and IMI. Each of the compounds was cleaved to the same eight urinary metabolites derived from the chloropyridinylmethyl moiety (i.e., chloropyridinecarboxylic acid and its methylthio-, hydroxy-, and N-acetylcysteinyl derivatives and glycine, O-glucuronide, and sulfate conjugates thereof). Three nitro- or cyano-containing fragments were identified from the rest of the molecule for IMI, NIT, and ACE and one for THI. IMI gave nitrosoguanidine, aminoguanidine, guanidine (desnitro), olefin, methyltriazinone, and hydroxy- and dihydroxyimidazole derivatives. NIT metabolism involved N-demethylation, conversion to a cyano derivative via a nitrosomethylene intermediate, and oxidation at the nitromethylene carbon to the carboxylic acid. THI yielded olefin, imine (descyano), descyano olefin, amide, and hydroxythiazolidine derivatives and a ring-opened and methylated THI sulfoxide. ACE formed N-desmethyl, acetamide, amide, chloropyridinylmethylamine, and N-methylchloropyridinylmethylamine derivatives. Despite their common metabolites, these neonicotinoids differ greatly in their molecular sites and rates of metabolism in mice.