Chloropyridinyl Neonicotinoid Insecticides:  Diverse Molecular Substituents Contribute to Facile Metabolism in Mice

Abstract

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, Oglucuronide, 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.

Biological Monitoring Method for Urinary Neonicotinoid Insecticides Using LC‐MS/MS and Its Application to Japanese Adults

“…When NEOs, especially dinotefuran and imidacloprid, are absorbed into the body, they are excreted in urine as an unchanged compound, because they have higher water solubility than organophosphorus and pyrethroids 10,11) . Thus, monitoring of urinary NEO, but not NEO metabolites, may contribute to a more precise estimation of the amount of NEO uptake into the human body.…”

Acetamiprid Accumulates in Different Amounts in Murine Brain Regions

“…In one in vivo experiment, ACE, imidacloprid, and thiacloprid were separately administered by intraperitoneal injection to mice at 10 mg/kg [1,2]. Levels of the neonicotinoids in the mice brains were then measured at different time-points.…”

“…This was followed soon thereafter by the chlorothiazolylmethyl insecticides (thiamethoxam and clothianidin) and a tetrahydrofuranylmethyl analog (dinotefuran) [1,2]. The insecticidal activity of neonicotinoids is primarily attributed to their action on nicotinic acetylcholine receptors (nAChRs) [3,4].…”

“…Shi et al [12] reported that concentrations of clothianidin and thiacloprid increase in the brain and liver when CYP enzymes are inhibited. Ford et al [1,2] also reported that ACE and its metabolic products were observed in brain, liver, plasma, and urine from ACE-treated rats. Thus, it would appear that ACE can pass through the blood-brain barrier.…”

Insecticidal and neuroblocking potencies of variants of the thiazolidine moiety of thiacloprid and quantitative relationship study for the key neonicotinoid pharmacophore

“…19) The high synergistic effect of compound 23 is crucially due to the sulfide moiety sensitive to the enzymatic oxidation in the absence of synergists, as observed in other neonicotinoid sulfide derivatives, 1,8) and Ford and Casida actually observed the facile oxidation of thiacloprid to the SO-derivative in the brain, liver and plasma in intraperitoneally administrated mice. 32) One of the major oxidation metabolic pathways for imidacloprid assures the hydroxylation at the C4/C5 position and the subsequent dehydration in plants, 33,34) mice, 32) houseflies 19) and human cytochrome. 35) In our earlier experiment, these metabolites showed lower insecticidal activity against American cockroaches.…”