METABOLISM OF 3,5-DIMETHYLPYRAZOLE-C¹⁴ IN THE RAT

¹ Biochemical Research Division, The Upjohn Company, Kalamazoo, Michigan

3,5-Dimethylpyrazole-C¹⁴ is absorbed completely from the gastrointestinal tract of fasted rats when administered as an aqueous suspension. Essentially all of the oral dose (95%) is found in the urine within 24 hours. It is converted completely (>99%) to 4 metabolites. Two metabolites, which together with their conjugated forms account for about 98% of the oral dose of 3,5-dimethylpyrazole, have been isolated in crystalline form and their structures determined. In 5 normal, fasted rats the average percentages excreted (± S.D.) as 5-methylpyrazole-3-carboxylic acid and its conjugete form were 13.1 ± 3.8 and 13.6 ± 4.4, respectively. The major metabolite, which was excreted to the extent of 70.8 ± 5.5% in fasted rats, has been unequivocally identified as conjugated 4-hydroxy-3, 5-dimethylpyrazole; it has been isolated from hydrolyzed rat urine in its unconjugated form. An unknown metabolite, which is formed to the extent of 1.3 ± 1.9% of the dose, was not detected in the urine of some of the rats studied.

From the urinary excretion data, the halflife for the appearance of C¹⁴ in the urine of the rat was determined to be about 2.4 hours; i.e., about 60% of the C¹⁴ is excreted during the first 3 hours.

The fate of 3,5-dimethylpyrazole in fasted rats compared to rats treated with corn oil and SKF-525A indicates that the inhibition of hypoglycemic activity by these agents probably cannot be explained by their effect on the absorption and/or metabolism of 3,5-dimethylpyrazole.