Metabolism of furametpyr. 1. Identification of metabolites and in vitro biotransformation in rats and humans

Urinary and fecal metabolites in male rats treated with a C-14-labeled fung icide, furametpyr [N-(1,3-dihydro-1, 1,3-trimethylisobenzofuran-4-yl)-5-chl oro-1,3-dimethylpyrazole-4-carboxamide, Limber] were purified by a combinat ion of chromatographic techniques, and chemical structures of 14 metabolite s were identified by spectroanalyses (NMR and MS). The major biotransformat ion reactions of furametpyr in rats were feued to be (1) N-demethylation, ( 2) oxidation of the methyl group at C3 of the pyrazole ring, (3) oxidation of the methyl group at C1 of the 1,3-dihydroisobenzofuran ring, (4) hydroxy lation at C3 of the 1,3-dihydroisobenzofuran ring, and (5) hydroxylation at C7 of the 1,3-dihydroisobenzofuran ring. In vitro metabolism by recombinan t human cytochrome P450 revealed that a major biotransformation in humans i s N-demethylation, catalyzed by CYP1A1, 1A2, 2C19, and 3A4.