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© 1984 Oxford University Press

research-article

Metabolism of [14C]Acetylisoniazid and [14C]Acetylhydrazine by the Rat and Rabbit

BARRY H. THOMAS1,, LARRY W. WHITEHOUSE and WALTER ZEITZ

Drug Toxicology Division, Bureau of Drug Research, Health and Welfare Canada Ottawa, Ontario KIA 0L2, Canada

Metabolism of [14C]Acetylisoniazid and [14C]Acctylhydrazine by the Rat and Rabbit Thomas, B. H., WHITEHOUSE, L. W., and ZEITZ, W. (1984). Fundam. Appl. Toxicol. 4, 646–653. Male rats and rabbits were singly dosed with either l-[14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acctyl-INH, 200 mg/kg po) or 1-[l4C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired 14CO2 were collected, and after 6 hr the animals were killed for the analysis of tissue 14C concentrations and covalent binding of 14C to hepatic protein. Rats excreted proportionately more 14C in urine and had lower 14C levels in their tissues compared to rabbits. When acetyl-INH was administered, covalent hepatic protein binding of the acetyl moiety was greater in the rabbit than the rat, but the opposite was observed when acetylhydrazine was administered. Analysis of blood and urine by TLC revealed that the rabbit more rapidly metabolized both acetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazine than did the rat. These observations suggest that higher amidase activity in the rabbit compared to the rat leads to faster conversion of acetyl-INH to acetylhydrazine which in turn leads to greater covalent binding and hepatotoxicity.


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