Metabolism of C14-Labeled Isoniazid in Vitamin B6-Deficient Rats

Boone, Irene U.; Magee, M; Turney, Donna Faye

doi:10.1016/s0021-9258(18)65191-9

Cited by 14 publications

(2 citation statements)

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“…17 The importance of pyridoxal in the prevention of INH-induced neurotoxicity has been demonstrated in a rat model of vitamin B 6 -deficient rats that were more susceptible to INH-induced neurotoxicity. 18 Genetic polymorphism of NAT-2 in man has been shown to give rise to slow, intermediate, and fast acetylators. 19 The slow acetylator phenotype has been shown to be important in the development of INH-induced peripheral neuropathies.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The primary site of acute INH-induced toxicity in human and animal models is the CNS. ,, The development of INH-induced neurotoxicity is linked to the depletion of the cellular reserve of pyridoxal, which subsequently leads to a depletion of GABA levels in the brain, resulting in excessive CNS stimulation and seizures. , In the clinic, pyridoxine (vitamin B 6 ) is co-administered with INH to counteract the INH-induced depletion of the pyridoxal pool . The importance of pyridoxal in the prevention of INH-induced neurotoxicity has been demonstrated in a rat model of vitamin B 6 -deficient rats that were more susceptible to INH-induced neurotoxicity …”

Section: Introductionmentioning

confidence: 99%

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Pharmacometabonomic Characterization of Xenobiotic and Endogenous Metabolic Phenotypes That Account for Inter-individual Variation in Isoniazid-Induced Toxicological Response

et al. 2012

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An NMR-based pharmacometabonomic approach was applied to investigate inter-animal variation in response to isoniazid (INH; 200 and 400 mg/kg) in male Sprague-Dawley rats, alongside complementary clinical chemistry and histopathological analysis. Marked inter-animal variability in central nervous system (CNS) toxicity was identified following administration of a high dose of INH, which enabled characterization of CNS responders and CNS non-responders. High-resolution post-dose urinary ¹H NMR spectra were modeled both by their xenobiotic and endogenous metabolic information sets, enabling simultaneous identification of the differential metabolic fate of INH and its associated endogenous metabolic consequences in CNS responders and CNS non-responders. A characteristic xenobiotic metabolic profile was observed for CNS responders, which revealed higher urinary levels of pyruvate isonicotinylhydrazone and β-glucosyl isonicotinylhydrazide and lower levels of acetylisoniazid compared to CNS non-responders. This suggested that the capacity for acetylation of INH was lower in CNS responders, leading to increased metabolism via conjugation with pyruvate and glucose. In addition, the endogenous metabolic profile of CNS responders revealed higher urinary levels of lactate and glucose, in comparison to CNS non-responders. Pharmacometabonomic analysis of the pre-dose ¹H NMR urinary spectra identified a metabolic signature that correlated with the development of INH-induced adverse CNS effects and may represent a means of predicting adverse events and acetylation capacity when challenged with high dose INH. Given the widespread use of INH for the treatment of tuberculosis, this pharmacometabonomic screening approach may have translational potential for patient stratification to minimize adverse events.

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Section: ■ Introductionmentioning

confidence: 99%