RT Journal Article
SR Electronic
T1 Factors affecting the metabolism of [14C]acetylhydrazine in rats.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 561
OP 566
VO 6
IS 5
A1 Wright, J M
A1 Timbrell, J A
YR 1978
UL http://dmd.aspetjournals.org/content/6/5/561.abstract
AB Some factors affecting the metabolism of the potent hepatotoxin, acetylhydrazine, were studied in rats. After ip administration of [14C]acetylhydrazine, 36% and 38% of the dose was recovered in the urine and as 14CO2, respectively. The major urinary metabolites were diacetylhydrazine and the pyruvic acid and alpha-oxoglutaric acid acetylhydrazones. The acetylation of acetylhydrazine to diacetylhydrazine was found to be dose-dependent and to be inhibited by coadministered isoniazid and p-aminosalicylic acid. Coadministered acetylisoniazid had no effect on acetylation. The proportion of acetylhydrazine recovered as 14CO2 presumably reflects the amount metabolized by the microsomal oxidation pathway, thought to be responsible for the toxicity, and also possibly by hydrolysis to acetate and hydrazine. This latter pathway could not be confirmed, as only a small proportion of hydrazine administered to rats was recovered. The inhibition of acetylation by p-aminosalicyclic acid, but not isoniazid, significantly increased the excretion of 14CO2, suggesting that isoniazid may also inhibit a pathway resulting in the production of 14CO2. These results indicate that the metabolism and hepatotoxicity of acetylhydrazine may be different when it is produced as a metabolite of isoniazid than when it is given alone.