Isoniazid and iproniazid are chemically similar drugs having different pharmacological effects; they may both cause liver damage after therapeutic doses are given. Isoniazid is still widely used for the treatment of tuberculosis, but iproniazid is now rarely used as an antidepressant.
The major routes of metabolism for isoniazid are acetylation to give acetylisoniazid, followed by hydrolysis to yield isonicotinic acid
and acetylhydrazine (figure 7.15). The acetylation of isoniazid in human populations is genetically determined and therefore shows a bimodal distribution (see page 135). Thus, there are two acetylator phenotypes, termed rapid and slow acetylators, which may be distinguished by the amount of acetylisoniazid excreted or by the plasma half-life of isoniazid.
Mild hepatic dysfunction, detected as an elevation in serum transaminases, is now well recognized as an adverse effect of isoniazid and occurs in 10-20% of patients. Possibly as many as 1 % of these cases progress to severe hepatic damage and it has been suggested that this latter, more severe form, of hepatotoxicity may have a different underlying mechanism. However, the greater incidence of hepatotoxicity reported in rapid acetylators has since been questioned. It seems that the incidence of the mild form of isoniazid hepatotoxicity is not related to the acetylator phenotype, but the incidence of the rarer, more severe form is more common in slow acetylators. However, initial suggestions that patients with the rapid acetylator phenotype (see page 135) were more susceptible to such damage, prompted a study of the relationship between metabolism and toxicity.
Animal studies revealed that both acetylisoniazid and acetylhydrazine were hepatotoxic, causing centrilobular necrosis in phenobarbital-pretreated animals. Conversely, pretreatment of animals with microsomal enzyme inhibitors reduced necrosis. Inhibition of the hydrolysis of acetylisoniazid (figure 7.15) with bis-p-nitrophenylphosphate (figure 5.32), an acyl amidase inhibitor, reduced its hepatotoxicity, but not that of acetylhydrazine. Further studies revealed that metabolism of acetylhydrazine by the microsomal mono-oxygenases was responsible for the hepatotoxicity, resulting in
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