Disposition of Nifurtimox and Metabolite Activity Against <i>Trypanosoma cruzi</i> using Rat Isolated Perfused Liver

González-Martín, G; Paulos, Claudio; Guevara, Alba; Ponce, Graciela

doi:10.1111/j.2042-7158.1994.tb03812.x

Cited by 6 publications

(4 citation statements)

References 3 publications

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“…A more recent ex vivo study, in which rat livers were perfused in recirculation mode with a solution of nifurtimox, demonstrated that almost no parent compound remained after a 2 h incubation period and that some highly polar metabolites had accumulated. Another notable finding in this study was that samples of perfusate over time retained most of the antiparasitic activity, 10 possibly suggesting the formation of a pharmacologically active metabolite.…”

Section: Introductionmentioning

confidence: 60%

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox

Lang

Schulz

Piel

et al. 2022

Chem. Res. Toxicol.

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The oral antiparasitic drug nifurtimox has been used to treat Chagas disease for more than 50 years. Historical studies determined that very little nifurtimox is excreted unchanged, but contemporaneous preclinical studies of radiolabeled nifurtimox found almost all of the radiolabel was rapidly excreted, suggesting that metabolism is extensive. Attempts to study nifurtimox metabolism have had limited success, yet this knowledge is fundamental to characterizing the pharmacokinetics and pharmacodynamics of the drug. We conducted in vitro studies using hepatic and renal sources with 14 C-labeled nifurtimox as substrate and obtained samples of urine, plasma, and feces from rats administered 2.5 mg/kg [ 14 C]-nifurtimox, and samples of human urine and plasma from phase 1 clinical studies in which participants received a single dose of 120 mg nifurtimox. Analysis of metabolites was done by high-performance liquid chromatography (HPLC)high-resolution mass spectrometry (HRMS) and HRMS/MS with offline liquid scintillation counting of radiolabeled samples. Surprisingly, only traces of a few metabolites were identified from in vitro incubations with hepatocytes and subcellular fractions, but more than 30 metabolites were identified in rat urine, mostly with atypical mass changes. We developed an HRMS scouting method for the analysis of human samples based on the sulfur atom in nifurtimox and the natural abundance of 34 S, as well as a characteristic tandem mass spectrometry (MS/MS) fragmentation of nifurtimox and metabolites. Fragmentation patterns on HRMS/MS were used to propose structures for 18 metabolites (22 including stereoisomers), and based on these structures, the six most abundant products were synthesized and the structures of the synthetic forms were confirmed by HRMS and two-dimensional nuclear magnetic resonance (2D NMR). Overall, we determined that the metabolism of nifurtimox is almost certainly not mediated by typical hepatic and renal drug-metabolizing enzymes, and instead is rapidly metabolized mainly by reduction or nucleophilic attack, with some evidence of oxidation. Knowledge of the most abundant metabolites of nifurtimox affords the possibility of future studies to investigate levels of exposure and possible drug−drug interactions.

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Section: Introductionmentioning

confidence: 60%

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox

Lang

Schulz

Piel

et al. 2022

Chem. Res. Toxicol.

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“…[86] Limited human data on NF metabolism, is primarily based on animal trials and proposed metabolites. [87][88] Human CYP isoforms and related enzymes involved in biotransformation remain unidentified, despite animal research suggesting their role. [87,89] NF's 50 % plasma protein binding is not expected to significantly impact drug interactions.…”

Section: Nifurtimoxmentioning

confidence: 99%

“…Under fed conditions, the time to reach C max (T max ) was 4 hours with a high‐fat meal causing a 68 % increase in C max , a 71 % increase in AUC, and a 1‐hour delay in T max. [86] Limited human data on NF metabolism, is primarily based on animal trials and proposed metabolites [87–88] . Human CYP isoforms and related enzymes involved in biotransformation remain unidentified, despite animal research suggesting their role [87,89] .…”

Section: Treatmentmentioning

confidence: 99%

Alternative Approaches for the Treatment of Chagas Disease

Chaudhary,

Rajge,

Khandale

et al. 2024

ChemistrySelect

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Chagas disease (CD), or American trypanosomiasis, caused by the parasitic protozoa Trypanosoma cruzi, is a substantial global health burden. This comprehensive review explored the multifaceted landscape of CD treatment, providing a historical perspective on the development and discontinuation of benznidazole (BNZ) and nifurtimox (NF), the primary medications. Efforts towards a pediatric version of BZN in Brazil address demographic‐specific treatments, while concerns over drug resistance prompt the exploration of alternative medications like Amiodarone, Allopurinol, Posaconazole, Ravuconazole, and Fexinidazole, which were clinically tested as antichagasic drugs. In recent years, some of the synthesized derivative (1,3‐thiazoles, 4‐thiazolidinones, 2‐styrylquinolines, imidazole‐containing nitrophthalazine, and some others) were found to better activity as compared to standard drug. Traditional herbal alternatives (Resveratrol, curcumin, 1,8‐cineole, β‐pinene, and some others) rooted in traditional practices show promise, with various plant extracts exhibiting anti‐parasitic properties. The frontier of nanomedicine unfolds with studies on solid nanomedicines, PLA‐nanoparticles, ZIF‐8, BNZ carriers, and PLGA nanoparticles, showcasing improved drug delivery systems and controlled release mechanisms. The absence of a definitive vaccine accentuates ongoing research in recombinant antigens, peptide‐based vaccines, and nanoparticle formulations, with notable candidates like TcG1, TcG2, TcG4, MASPpep‐KLH, adenovirus vectors, Tc24 protein, and integrin activators. A novel strategy combining a recombinant protein vaccine with low dose BZN treatment presents promising results in a mouse model, emphasizing the urgency for further research and potential advancements in CD therapeutics.

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“…Interestingly, in this study Cmax increased 68%, AUC increased 71%, and Tmax increased by 1 hour after a high-fat meal compared to fasted conditions. 96 Animal liver experiments of NF metabolism have suggested a number of metabolites 97 , but this aspect has only been studied in a limited number of humans, with preliminary confirmation of the metabolites observed in animal experiments and further observation of a range of minor metabolites 98 . Data from animal studies also suggests that CYP enzymes are responsible for NF metabolism, but no human data is publicly available identifying specific CYP isoforms, or associated enzymes, responsible for biotransformation 98,99 .…”

Section: Nifurtimox Clinical Pharmacologymentioning

confidence: 99%

Review of pharmacological options for the treatment of Chagas disease

Lascano

Bournissen

Altcheh

2021

Brit J Clinical Pharma

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Introduction: Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment, benznidazole (BZN) and nifurtimox (NF). Treating CD infected patients, especially children and women of reproductive age, is vital in order to prevent long term sequelae, such as heart and gastrointestinal dysfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Finally, treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response.Areas covered: This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Conclusion:Early diagnosis and treatment of CD, especially in pediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drugs development.

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Disposition of Nifurtimox and Metabolite Activity Against Trypanosoma cruzi using Rat Isolated Perfused Liver

Cited by 6 publications

References 3 publications

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox

Structural and Mechanistic Investigation of the Unusual Metabolism of Nifurtimox

Alternative Approaches for the Treatment of Chagas Disease

Review of pharmacological options for the treatment of Chagas disease

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