Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydrazine metabolites

Jerry R. Mitchell, Unnur P. Thorgeirsson, Martin Black, John A. Timbrell, Wayne R. Snodgrass, William Z. Potter, David J. Jollow, Harry R. Keiser

Research output: Contribution to journalArticle

240 Scopus citations

Abstract

Approximately 10% to 20% of isoniazid recipients manifest biochemical evidence of liver injury. A smaller number of patients develop clinically overt hepatitis. Isoniazid is metabolized in man at extremely variable rates, and the rate is under genetic control. Two separate clinical studies have noted a possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug. For this reason, 21 patients who had recovered from probable isoniazid hepatitis and 5 patients who previously had manifested biochemical evidence of mild isoniazid liver injury were genetically phenotyped as rapid or slow isoniazid acetylators by the sulfamethazine method. The rapid phenotype was found in 86% of patients with probable hepatitis and in 60% of the possible ones, whereas the expected frequency was 45%. Examination of isoniazid metabolites revealed that rapid acetylators hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. We suggest that release of the hepatotoxic hydrazino moiety of isoniazid in man is responsible for isoniazid liver injury.

Original languageEnglish (US)
Pages (from-to)70-79
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume18
Issue number1
DOIs
StatePublished - Jul 1975
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Mitchell, J. R., Thorgeirsson, U. P., Black, M., Timbrell, J. A., Snodgrass, W. R., Potter, W. Z., Jollow, D. J., & Keiser, H. R. (1975). Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydrazine metabolites. Clinical Pharmacology and Therapeutics, 18(1), 70-79. https://doi.org/10.1002/cpt197518170