Metabolism of metofluthrin in rats: I. Identification of metabolites

Abstract

<p>1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (<i>Z/E</i>)-(1<i>R</i>)-<i>trans-</i>2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has <i>E/Z</i> isomers at prop-1-enyl group.</p> <p>2. Rats were orally dosed with each [¹⁴C]-labelled <i>E/Z</i> isomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed with <i>Z</i>-isomer and <i>E</i>-isomer, respectively.</p> <p>3. Major metabolic reactions were cleavage of ester linkage, <i>O</i>-demethylation, hydroxylation, epoxidation or reduction of double bond, glutathione conjugation and its further metabolism, hydroxylation of epoxide and formation of lactone ring. Notably, the acid side, 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylic acid, was much more variously metabolised compared to chrysanthemic acid, the acid side of the known pyrethroids.</p> <p>4. Major metabolites for <i>Z</i>-isomer mostly retained ester linkage with 1,2-dihydroxypropyl group and/or 2-methylalcohol of cyclopropane ring, while most of those for <i>E</i>-isomer received hydrolysis of the ester linkage without oxidation at the 1-propenyl group or the <i>gem</i>-methyl groups, suggesting epoxidation and hydroxylation could occur more easily on <i>Z</i>-isomer.</p> <p>5. As the novel metabolic pathways for pyrethroids, isomerisation of ω-carboxylic acid moiety, reduction or hydration of double bond and cleavage of cyclopropane ring via epoxidation were suggested.</p