Metabolism of Isoniazid

Hofstra AH, Li-Muller SM, Uetrecht JP. Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus. Drug Metab Dispos 1992 20(2) 205-210. 

E. Albano, A. Tomasi, Spin Trapping of Free Radical Intermediates Produced during the Metabolism of Isoniazid and Iproniazid in Isolated Hepatocytes, Biochem. Pharmacol. 1987, 18, 2913-2920. 

Metabolism of isoniazid, especially acetylation by liver /V-acetyltransferase, is genetically determined (see Chapter 4). The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption. 

Figure 7.24 Metabolism of isoniazid. The acetylhydrazine released by the hydrolysis of acetylisoniazid is further metabolized to a reactive intermediate thought to be responsible for the hepatotoxicity.

Hughes HB, Biehl JP, Jones AP, Schmidt LH. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am Rev Tuberc 1954 70 266-273. 

Data with a polymodal distribution If we give a series of patients a standard oral dose of the anti-tuberculosis drug isoniazid, obtain a blood sample from each individual 6 h later and determine the isoniazid concentrations of those samples, the results will probably look like Figure 3.1. The data are bimodal, because the metabolism of isoniazid is genetically controlled and we all fall into one of two groups - fast or slow metabolizers. The fast metabolizers form the cluster at the low end of the concentration scale and the slow metabolizers form a distinct group with higher levels. 

The classical model of drug metabolism by acetylation is the tuberculostatic drug isoniacide (isonicotinic acid hy-drazide). The metabolism of isoniazide has two interesting aspects Firstly, non-enzymatic hydrolysis of the acetyl metabolite releases acetylhydrazine, which in turn is toxic. This, then, is an example of detrimental drug metabolism (Figure 2.30a, b). 

Figure 2.30. Metabolism of isoniazid. a Acetylation, b Hydrolysis of the acetyl conjugate leads to liver toxicity, c Distribution of acetylation rates in the population.

Barbiturates which induce Uver drug-metaboUzing enz)mes increase the rate of metabolism of isoniazid, rifampicin, or combined antituberculosis treatment, since they may result in accelerated breakdown of these drugs (52). 

Side effects caused by isoniazid, rifampin, pyrazinamide, and ethambutol are common and can include hepatotoxic-ity, peripheral neuropathy, optic neuritis, and Gl side effects. All four agents can potentially be hepatotoxic, but this side effect is most frequently associated with isoniazid and rifampin. Peripheral neuropathy is most commonly associated with isoniazid, whereas optic neuritis is associated with ethambutol. The metabolism of isoniazid is genetically predetermined. Patients of Scandinavian, European, and African descent metabolize isoniazid slower (slow acetylators) and are therefore more predisposed to hepatotoxicity and peripheral neuropathy due to isoniazid. Fast acetylators include people of Asian or American Indian descent and are less predisposed to these adverse effects. 

Another example is the metabolism of isoniazid, a drug used to treat tuberculosis. This drug is metabolized by acetylation and 50% of the population acetylate it slowly, which can lead to toxic effects. 

Genotypic variants occur with regard to the metabolism of isoniazid. What other drugs exhibit such variation, and what enzymes are involved in their metabolism What are the clinical consequences of genetic polymorphisms in drug metabolism The Skill Keeper Answer appears at the end of the chapter. 

The reasons for the hepatotoxicity are not fully understood but rifampicin or isoniazid alone can cause liver damage by their own toxic action. One suggestion is that the rifampicin alters the metabolism of isoniazid, resulting in the formation of hydrazine, which has proven to be hepatotoxic. Higher plasma levels of hydrazine are said to occur in slow acetylators of isoniazid, but one study failed to confirm that this is so. There has certainly been at least one fatality caused by this combina-tion. The manufacturers of rifampicin advise that caution is particularly needed in patients with impaired liver function, the elderly, malnourished patients, and children under two years of age. After baseline LFTs, further tests are only needed if fever, vomiting, or jaundice occur, or if the patient deteriorates. However, the manufacturers of isoniazid suggest that liver function tests should be reviewed regularly in patients on combined treatment. ... 

Metabolism of isoniazid. (Modified after Ellard and Gammon 1976 Mitchel et al. 1976)... 

Susceptibility factors Genetic Hepatic metabolism of isoniazid involves acetylation to acetylisoniazid by 7V-acetyltransferase... 

The hypothesis that human metabolism of isoniazid is controlled by two allelic genes and that the slow inactivator is homozygous for an autosomal recessive gene was reexamined in the light of these data by Evans... 

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