FACTORS AFFECTING METABOLISM OF [ACETYLHYDRAZINE-C-14 IN RATS

  • 1 January 1978
    • journal article
    • research article
    • Vol. 6  (5) , 561-566
Abstract
Some factors affecting the metabolism of the potent hepatotoxin, acetylhydrazine [a metabolite of the hepatotoxic anti-tuberculosis drug isoniazid], were studied in rats. After i.p. 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 dose-dependent and inhibited by coadministered isoniazid and p-aminosalicyclic 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 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 inhibit a pathway resulting in the production of 14CO 2. The metabolism and hepatotoxicity of acetylhydrazine may be different when it is produced as a metabolite of isoniazid than when it is given alone.