Studies in detoxication. 75. Further observations on the metabolism of hydrazides of aromatic acid

Abstract

The fate in the rabbit of the following compounds was investigated; benzohydrazide and its p-chloro, p-methyl and m- and p-hydroxy derivatives; 1-acetyl-2-m and -p-hydroxybenxoylhydrazines and their anhydrides; 2-m- and -p-hydroxyphenyl-5-methyl-l-oxa-3:4-diazoles. Benzohydrazide, p-chlorobenzohydrazide and p-methylbenzohydrazide were lethal to rabbits in oral doses of just over 100 mg/kg and were metabolized to the corresponding hippuric acids, which were isolated from the urine. Hydroxylation of the benzene ring and acetylation of the hydrazide group were not detected. p-Hydroxybenzohydrazide and its acetyl derivative and 1-acetyl-2-p-hydroxybenzoylhydrazine were relatively non-toxic and were metabolized by direct conjugation with glucuronic and sulfuric acids. m-Hydroxybenzohydrazide was intermediate in toxicity between benzohydrazide and p-hydroxybenzohydrazide, and was metabolized mainly by direct conjugation but partly by hydrolysis to m-hydroxybenzoic acid. 2-m- and -p-Hydroxyphenyl-5-methyl-l-oxa-3:4-diazoles were relatively non-toxic and were metabolized by direct conjugation mainly with glucuronic acid. It is suggested that the toxicity of benzohydrazide and its p-chloro and p-methyl derivatives is due to release of hydrazine in vivo.