Metabolism of tetramethrin isomers in rat: IV. Tissues responsible for formation of reduced and hydrated metabolites

1. To identify the sites of formation of the reduced metabolites, 3-hydroxy-cyclohexane-1,2-dicarboximide (3-OH-HPI-1 and -2), 1,2-cyclohexanedicarboxylic acid (TCDA) and 1-hydroxy-1,2-cyclohexanedicarboxylic acid (1-OH-HPA), in rat treated with 14C-labelled (1RS, trans)-tetramethrin, 3,4,5,6-tetrahydrophthalimidomethyl (1RS, trans)-chrysanthemate], bile-duct cannulated animals were orally or intravenously administered 14C-labelled 3,4,5,6-tetrahydrophthalimide (TPI) or 3,4,5,6-tetrahydrophthalic acid (THPA), precursors of these metabolites, and bile, urine and faeces were collected for analysis. 2. 3-OH-HPI-1 and 3-OH-HPI-2, which are cis-form reduced metabolites, and 1-OH-HPA were detected in bile and urine samples of the bile-cannulated rat treated intravenously and orally with 14C-labelled TPI, indicating their formation in tissues or blood. TCDA, a trans-form reduced metabolite, was not detected in bile, urine or faeces of the bile-cannulated rat treated intravenously with 14C-THPA, but was found in the faeces after oral application, indicating formation in the gastrointestinal tract. 3. To clarify whether 1-OH-HPA is produced from THPA via TCDA (hydroxylation via reduction) or by direct addition of H2O to its double bond (hydration), rats were orally administered 14C-labelled TCDA, and metabolites in urine and faeces were analysed. The observed lack of 1-OH-HPA indicated formation by direct addition of H2O to the double-bond of THPA. 4. To specify which tissues form reduced and hydrated metabolites, in vitro metabolism studies were carried out. Reduction to the cis-form was found to take place in blood cells, reduction to the trans-form took place in the gastrointestinal tract contents, and hydration took place in the liver and the intestinal tract contents.