Species-Specific Detoxification Metabolism of Fenpyroximate, a Potent Acaricide

Abstract

Abstract The mode of selective toxicity of fenpyroximate ( tert -butyl ( E )-α-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)- p -toluate), a potent acaricide, was studied with respect to its detoxification metabolism. Among its metabolites examined, only ester hydrolyzed metabolites completely lost the inhibitory activity toward NADH–ubiquinone oxidoreductase, which suggested that ester hydrolysis was the key step in detoxification. After a single oral administration of fenpyroximate to rats, two labile intermediates (metabolites A and B) as well as ester hydrolyzed metabolites were found in the liver and plasma as the major metabolites. These intermediates were also observed in an in vitro metabolism system employing rat liver S-9 (9000 g supernatant) fraction under the presence of diisopropyl fluorophosphate, a carboxyesterase inhibitor. Metabolites A and B were isolated and identified as 1-hydroxymethyl-1-methylethyl ( E )-α-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)- p -toluate and 2-hydroxy-2-methylpropyl ( E )-α-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)- p -toluate, respectively. Under slightly basic conditions or in rat plasma, metabolite A was stoichiometrically and nonenzymatically converted to metabolite B most likely via intramolecular transesterification. The rate of in vitro metabolite A production was approximately 10 times greater than that of direct carboxyesterase hydrolysis of fenpyroximate; metabolite B was hydrolyzed approximately 100 times faster than fenpyroximate by carboxyesterase. Therefore, it is presumed that fenpyroximate is hydrolyzed principally via hydroxylation of fenpyroximate to metabolite A followed by transesterification to metabolite B in the rat. Hydroxylation of fenpyroximate to metabolite A was observed not only in rat liver, but also in mouse, rabbit, crab-eating monkey, carp, quail liver, and Spodoptera litula mid gut. Neither tertiary butyl ester hydrolysis nor metabolite A formation was detected in Tetranychus urticae Koch (two spotted spider mites), a fenpyroximate-sensitive organism in vivo and in vitro . Consequently, selectivity of fenpyroximate between spider mites and non-target organisms, especially mammals, would be attributable to the species-specific detoxification, ester hydrolysis via microsomal hydroxylation followed by intramolecular transesterification.