1991 Volume 16 Issue 2 Pages 201-210
Metabolism of (R)-(E)-1-(2, 4-dichlorophenyl)-4, 4-dimethyl-2-(1, 2, 4-triazol-1-yl)-1-penten-3-ol [designated as (R)-E], a major ingredient of diniconazole, was examined in rats after repeated oral administration. Effect of diniconazole on hepatic enzymes was also examined in vivo and in vitro. When (R)-E labeled with 14C at the triazole ring was orally administered once daily to male and female rats at 125mg/kg for 14 successive days (Day 0 to Day 13), 14C was slowly excreted into urine and feces for an initial few days, and faster thereafter to be completely eliminated from the body by Day 20. 14C-Tissue levels were higher on Days 1 and 6 but decreased to constant levels on Days 10 and 14. The 14C-tissue levels decreased to 1μg (R)-E equivalent/g tissue or less on Day 20, and no bioaccumulation or bioretention of 14C was observed in any tissues. Main metabolites produced by oxidation at the methyl group were found in Day 0-3 excreta as well as in Day 11-14 excreta. After single oral administration of diniconazole at 125mg/kg, the content of hepatic microsomal cytochrome P-450 had markedly decreased at 3hr, recovered at 8hr, and significantly increased at 24hr. Comparative effects were observed on microsomal drug-metabolizing activities, while no effects were found on the contents of hepatic mitochondrial cytochromes and enzyme activities of the electron transfer system. Diniconazole yielded typical Type II binding spectra with rat hepatic microsomal cytochrome P-450 and inhibited aniline hydroxylation non-competitively.
