Effects of Isoniazid and Its Metabolites on Phenytoin Biotransformation in Isolated Rat Hepatocytes

Abstract

The inhibitory effects of isoniazid, its metabolites and related compounds on phenytoin biotransformation were studied in an isolated rat hepatocyte system. Oxidation of phenytoin was inhibited strongly by isoniazid, acetylhydrazine, benzoylhydrazine and phenylhydrazine, and weakly (but significantly) by acetylisoniazid and hydrazine. Isonicotinic acid and diacetylhydrazine showed no effect. These observations may indicate that active hydrazine compounds are ones which can give a relatively significant rise to reactive intermediates such as radicals, diazene compounds or their reratives during the oxidation metabolism. On the other hand, glucuronidation of the oxidized metabolite, 5-phenyl-5- (p-hydroxyphenyl) hydantoin, was not affected by isoniazid.