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In Vivo. 2011 Sep-Oct;25(5):803-12.

Association of isoniazid-metabolizing enzyme genotypes and isoniazid-induced hepatotoxicity in tuberculosis patients.

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  • 1Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan.

Abstract

BACKGROUND:

Isoniazid (INH), a key drug of antituberculosis therapy, is metabolized by arylamine N-acetyltransferase2 (NAT2), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase (GST). We studied the possible influence of genetic polymorphisms of INH-metabolizing enzymes on serum concentrations of INH and its metabolites, as well as on the incidence of hepatotoxicity.

PATIENTS AND METHODS:

A total of 144 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their NAT, CYP2E1 and GST genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Blood samples were collected from the patients and serum concentrations were determined by HPLC. The severity of hepatotoxicity was judged by the increases in either aspartate aminotransferase or alanine aminotransferase levels from the upper limit of the corresponding normal range.

RESULTS:

Incidence of hepatotoxicity was highest in pulmonary tuberculosis patients with the slow acetylator (SA) phenotype and lowest in those with the rapid acetylator (RA) phenotype, although no clear relationship of genetic polymorphism of INH-metabolizing enzymes on the severity of hepatotoxicity were confirmed.

CONCLUSION:

The risk of side-effects, such as hepatic disorder, may rise in these patients with an SA phenotype, because of an increase in serum INH concentration. The evidence presented in this study, albeit based on the examination of a low number of patients, suggests that a safe INH dosage for tuberculosis patients with SA phenotype should be less than the dosage which is usually recommended for tuberculosis patients.

PMID:
21753138
[PubMed - indexed for MEDLINE]
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