Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients

Abstract

An HPLC method is described for measurement of plasma hydrazine (Hz) concentrations (CHz) at the same time as isoniazid (INH) levels (CINH). Study has been made of CHz during 2-5 after dose in healthy adults (A, n = 34), in adult pulmonary TB patients (B, n = 18) and in paediatric tuberculous meningitis patients (C, n = 25). Although the population has about equal proportions of 'slow' (52%) and 'fast' acetylators, in none of the groups could a correlation be shown between CHz levels or rates of Hz accumulation and any measure of acetylator type. Consequently Hz must be derived both from INH and from its metabolites during the first hours post-dose. For group A and ca. 70% of groups B and C a constant and maximal fraction of dose (ca. 0.6% for adults and 0.4% for paediatric patients) appeared as Hz at 4-5 h. For group B patients small pre-dose concentrations increased with duration of treatment. Four patients in group B showed the highest levels of CHz and rates of Hz accumulation some three times greater than the rest; all four had been identified as alcoholics and one showed evidence of hepatotoxicity at CHz (5 h) = 1.3% of dose. Amongst group C (9/25) episodes of high CHz greater than 0.5% of dose occurred during the first weeks of treatment and one developed CHz ca. 100 ng/ml = 1.3% of dose coincidentally with indications of hepatic damage.

Isoniazid: Metabolic Aspects and Toxicological Correlates

“…The amount of HZ has been found to be far inferior to that of the other hydrazines (AcHZ, DiAcHZ), but the metabolite has been detected in the tissues and plasma [56]. Gent et al [68] and Donald et al [69] have shown that HZ is also produced in children who receive INH, and the exposure to this metabolite may increase during the first weeks of treatment. The reaction involving AcINH yields INA and AcHZ, which is then deacetylated to HZ 2 or diacetylated to 1,2-diacetylHZ [70,71].…”

Antituberculosis drug‐induced hepatotoxicity: Concise up‐to‐date review

“…Most previous research has focused on the hypothesis that acetylhydrazine is the toxic metabolite of isoniazid 32,44 . More recent studies, however, suggest that hydrazine, and not isoniazid or acetylhydrazine, is most likely to be the cause of isoniazid‐induced hepatotoxicity 30,45–47 . Hydrazine toxicity has been described as early as 1908 and is known to cause irreversible cellular damage 48 .…”

“…32,44 More recent studies, however, suggest that hydrazine, and not isoniazid or acetylhydrazine, is most likely to be the cause of isoniazidinduced hepatotoxicity. 30,[45][46][47] Hydrazine toxicity has been described as early as 1908 and is known to cause irreversible No incidence: case-control study. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATDH, antituberculosis drug-induced hepatotoxicity; BMI, body-mass index; ND, not done; ULN, upper limit of normal (based on WHO criteria: ULN = 50 IU/L).…”

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

“…A few cases may be due to allergic-type hypersensitivity reactions with prominent eosinophilia and rash. 39,40 While testing baseline and follow-up serum ALT and bilirubin levels before beginning INH therapy is desirable in all patients, it is strongly recommended for patients with an underlying liver disorder such as chronic hepatitis B and C, alcoholic hepatitis and cirrhosis, in patients who regularly consume alcohol, those with HIV infection being treated with HAART, pregnant women, and those who are up to 3 months postpartum. 41 INH should be discontinued when jaundice and/or hepatitis symptoms are reported and ALT is at least three times the ULN, or if ALT is at least five times the ULN in the absence of symptoms.…”