Iproniazid hepatotoxicity

The metabolic fate of isoniazid and iproniazid, two isonicotinoylhydra-zides, has been extensively studied, and it has been shown that metabolic hydrolysis represents an important step in their toxification. Isoniazid (4.269) is employed as a first-line tuberculostatic drug, but prolonged therapy is associated in 1 -2% of patients with significant hepatotoxicity. Isoniazid can be metabolized by either of two primary pathways, hydrolysis and direct -acetylation. Isonicotinic acid (4.271), the product of hydrolysis, can be formed either di-... 

Iproniazid (4.272) was originally synthesized as a tuberculostatic drug but was found to be an antidepressant due to its inhibitory effect on monoamine oxidase. However, this compound had to be withdrawn from clinical use due to a high incidence of hepatotoxicity. The metabolism and the mechanism of toxification of iproniazid were found to be comparable to those of... 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

The toxic effects of the MAOIs are more varied and potentially more serious than those of the other classes of antidepressants in common use. Hepatotoxicity has been reported to occur with the older hydrazine type of MAOIs and led to the early demise of iproniazid the hepatotoxicity does not appear to be related to the dose or duration of the drug administered. 

Hydrazines. The hydrazines have only historic significance. The entire group of MAOIs was discovered through the euphoric side effect of isoniazid (8.36, isonicotinyl-hydrazide), a successful antituberculotic drug introduced in 1952. Iproniazid (8.37) is the corresponding isopropyl derivative. All of the hydrazides are highly hepatotoxic, and are no longer available. 

This is an uncommon reaction, most frequently associated with iproniazid, a hydrazine-based MAOl that has been removed from general use. The reaction seemed to be related to the liberation of free hydrazine and does not occur with nonhydrazine MAOIs. The risk of hepatotoxicity with currently available hydrazine MAOIs (phenelzine, isocarboxazid) is extremely low. 

Figure 7.25 Metabolism of iproniazid. The isopropylhydrazine moiety released by hydrolysis is further metabolized to a reactive intermediate thought to be responsible for the hepatotoxicity.

Thus, the hepatotoxicity of iproniazid and isoniazid may involve the alkylation or acylation of tissue proteins and other macromolecules in the liver. How these covalent interactions lead to the observed hepatocellular necrosis is at present not understood. 

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Iproniazid 24, an alkyl analog of the antituberculous drug isoniazid 25 (Figure 2.8), surprisingly showed mood-improving activity in several depressed tuberculosis patients, which turned out to result from a monoamine oxidase (MAO) inhibitory activity. Since the compound was already registered as an antituberculosis drug and since it constituted the very first effective treatment of depression, more than 400 000 patients received it within only one year after the first announcement of its antidepressant activity [2, 33], Later it was withdrawn from therapy, due to hepatotoxic side effects. 

The early reports of hepatotoxicity with iproniazid led to the synthesis of non-hydrazine inhibitors, and a report from 19 French drug surveillance centers (26) has reaffirmed the frequency and severity of this adverse effect. There were 91 cases of hepatitis due to all antidepressants (11 with iproniazid) over 5 years. Cytolytic reactions occurred in 11 patients treated with iproniazid 5 died. There was a high titer of antimitochondrial antibodies (M6) in five patients. 

Numerous studies have demonstrated an apparent relationship between metabolite formation and toxicity. The N-hydroxylation of phenacetin may play a role in drug-induced hepatic necrosis . Similarly, N-hydroxylation may mediate acetaminophen hepatotoxicity . Acetylhydrazine and isopropylhydrazine, metabolites of isoniazid and iproniazid, may initiate hepatotoxicity through covalent binding of an electrophilic intermediate (see Chapter 32) . 

Thus the hepatotoxicity of iproniazid and isoniazid may involve the alkylation or acylation of tissue... 

This drug has three times the potency of iproniazid and apparently greatly reduced hepatotoxicity. Tables II and III, which are taken from Zeller s... 

The disoovery of MAOIs resulted from a search for derivatives of Isoniazid (isonlootinlo aold hydrazide) (Fig. 21.25) with antitubercular activity. During clinical trials with this hydrazine derivative, a rather consistent beneficial effect of mood elevation was noted in depressed patients with tuberculosis. Although no longer used clinically, iproniazid (Fig. 21.25), the first derivative to be synthesized, was found to be hepatotoxic at dosage levels required for antituberoular and antidepressant activity. The antidepressant activity of iproniazid, however, prompted a searoh for other MAOIs, whioh resulted in... 

Timbrell, J. A. (1979). The role of metabolism in the hepatotoxicity of isoniazid and iproniazid. Drug Metab. 

---