Metabolic fate of hydrazine

Springer, David L.; Krivak, Brenda M.; Broderick, David; Reed, Donald J.; Dost, Frank N.

doi:10.1080/15287398109530047

Cited by 20 publications

(5 citation statements)

References 11 publications

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“…A significant proportion has also been shown to be metabolised to nitrogen detected in the expired air (Springer et al 1981;Nelson and Gordon 1982). However, in all studies a large proportion of the hydrazine dose was not accounted for.…”

Section: Introductionmentioning

confidence: 97%

Proton NMR spectroscopic studies on the metabolism and biochemical effects of hydrazine in vivo

Sanins

Timbrell

Elcombe³

et al. 1992

Arch Toxicol

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The metabolism and disposition of hydrazine and its effects on endogenous metabolites has been studied in rats by the use of high resolution proton NMR spectroscopy of urine. Several metabolites of hydrazine were detected, notably acetyl- and diacetylhydrazine and a cyclised metabolite which results from a hydrazone formed from 2-oxoglutarate and hydrazine. Effects of hydrazine on endogenous metabolites in urine and plasma were also observed; notably a dose-related increase in urinary taurine, a dose-related increase in urinary and plasma lactate, increases in urinary alpha-alanine, beta-alanine, methylamine and a decrease in urinary 2-oxoglutarate. This study has indicated the utility of using high resolution proton NMR spectroscopy to analyse urine for both metabolites and endogenous compounds after exposure of animals to toxic substances.

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Section: Introductionmentioning

confidence: 97%

Proton NMR spectroscopic studies on the metabolism and biochemical effects of hydrazine in vivo

Sanins

Timbrell

Elcombe³

et al. 1992

Arch Toxicol

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“…31 In fact, radicals have been detected in the microsomal oxidation of hydrazines,32 and nitrogen evolution has been recorded. 33 Interestingly, other hydrazine antidepressants, including iproclozide (Chart I), have been found to cause fulminant hepatitis in several patients. 34 The structural feature of iproclozide which is common to iproniazid is the isopropylhydrazine moiety, and isopropylhydrazine probably is a major hydrolytic metabolite of iproclozide.…”

Section: Introductionmentioning

confidence: 99%

Metabolic activation and drug toxicity

Nelson¹

1982

J. Med. Chem.

190

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“…In a preparatory step, the existing PBPK model of isoniazid was revised and extended with an endogenous hydrazine detoxification reaction to account for experimentally identified pathways. 25 , 26 The simulated plasma concentrations of isoniazid and its metabolites are in excellent agreement for fast and slow acetylators (Fig. 3a, b ).…”

Section: Resultsmentioning

confidence: 63%

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation

et al. 2018

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Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis, which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

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Metabolic fate of hydrazine

Cited by 20 publications

References 11 publications

Proton NMR spectroscopic studies on the metabolism and biochemical effects of hydrazine in vivo

Proton NMR spectroscopic studies on the metabolism and biochemical effects of hydrazine in vivo

Metabolic activation and drug toxicity

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation

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