Cargando…
In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites
BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurtimox in vivo. METHODS: We investigated the exposure and excretion pathways of [(...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Bentham Science Publishers
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661964/ https://www.ncbi.nlm.nih.gov/pubmed/37592798 http://dx.doi.org/10.2174/1389200224666230817114758 |
_version_ | 1785148495906209792 |
---|---|
author | Schulz, Simone I. Lang, Dieter Schmuck, Gabriele Gerisch, Michael Bairlein, Michaela Fricke, Robert Stass, Heino |
author_facet | Schulz, Simone I. Lang, Dieter Schmuck, Gabriele Gerisch, Michael Bairlein, Michaela Fricke, Robert Stass, Heino |
author_sort | Schulz, Simone I. |
collection | PubMed |
description | BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurtimox in vivo. METHODS: We investigated the exposure and excretion pathways of [(14)C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds in vitro. RESULTS: In rats, orally administered nifurtimox was rapidly absorbed (t(max) 0.5 h) and eliminated (t(½) 1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed versus fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P-450 enzymes and drug transporters were identified in vitro. CONCLUSION: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug. |
format | Online Article Text |
id | pubmed-10661964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Bentham Science Publishers |
record_format | MEDLINE/PubMed |
spelling | pubmed-106619642023-11-21 In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites Schulz, Simone I. Lang, Dieter Schmuck, Gabriele Gerisch, Michael Bairlein, Michaela Fricke, Robert Stass, Heino Curr Drug Metab Drug Design, Discovery and Therapy, Drug Delivery, Pharmacology, Drug Metabolism BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurtimox in vivo. METHODS: We investigated the exposure and excretion pathways of [(14)C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds in vitro. RESULTS: In rats, orally administered nifurtimox was rapidly absorbed (t(max) 0.5 h) and eliminated (t(½) 1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed versus fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P-450 enzymes and drug transporters were identified in vitro. CONCLUSION: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug. Bentham Science Publishers 2023-10-17 2023-10-17 /pmc/articles/PMC10661964/ /pubmed/37592798 http://dx.doi.org/10.2174/1389200224666230817114758 Text en © 2023 Bentham Science Publishers https://creativecommons.org/licenses/by/4.0/© 2023 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode) |
spellingShingle | Drug Design, Discovery and Therapy, Drug Delivery, Pharmacology, Drug Metabolism Schulz, Simone I. Lang, Dieter Schmuck, Gabriele Gerisch, Michael Bairlein, Michaela Fricke, Robert Stass, Heino In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites |
title |
In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites |
title_full |
In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites |
title_fullStr |
In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites |
title_full_unstemmed |
In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites |
title_short |
In vivo Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites |
title_sort | in vivo metabolism of nifurtimox and the drug-drug interaction potential including its major metabolites |
topic | Drug Design, Discovery and Therapy, Drug Delivery, Pharmacology, Drug Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661964/ https://www.ncbi.nlm.nih.gov/pubmed/37592798 http://dx.doi.org/10.2174/1389200224666230817114758 |
work_keys_str_mv | AT schulzsimonei invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites AT langdieter invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites AT schmuckgabriele invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites AT gerischmichael invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites AT bairleinmichaela invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites AT frickerobert invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites AT stassheino invivometabolismofnifurtimoxandthedrugdruginteractionpotentialincludingitsmajormetabolites |