Cargando…

Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis

Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous es...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Bing, Parker, Robert B., Meibohm, Bernd, Temrikar, Zaid H., Srivastava, Ashish, Laizure, S. Casey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704628/
https://www.ncbi.nlm.nih.gov/pubmed/36441753
http://dx.doi.org/10.1371/journal.pone.0278111
_version_ 1784840092695658496
author Yang, Bing
Parker, Robert B.
Meibohm, Bernd
Temrikar, Zaid H.
Srivastava, Ashish
Laizure, S. Casey
author_facet Yang, Bing
Parker, Robert B.
Meibohm, Bernd
Temrikar, Zaid H.
Srivastava, Ashish
Laizure, S. Casey
author_sort Yang, Bing
collection PubMed
description Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous esterases in the intestines and other tissues, but the specific enzymes involved are unknown. We hypothesized based on its structure and extensive presystemic metabolism that DMF would be a carboxylesterase substrate subject to interaction with alcohol. We sought to determine the enzymes(s) responsible for the extensive presystemic metabolism of DMF to MMF and the effect of alcohol on its disposition by conducting metabolic incubation studies in human recombinant carboxylesterase-1 (CES1), carboxylesterase-2 (CES2) and human intestinal microsomes (HIM), and by performing a follow-up study in an in vivo mouse model. The in vitro incubation studies demonstrated that DMF was only metabolized to MMF by CES1. Consistent with the incubation studies, the mouse pharmacokinetic study demonstrated that alcohol decreased the maximum concentration and area-under-the-curve of MMF in the plasma and the brain after dosing with DMF. We conclude that alcohol may markedly decrease exposure to the active MMF metabolite in the plasma and brain potentially decreasing the effectiveness of DMF in the treatment of RRMS.
format Online
Article
Text
id pubmed-9704628
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-97046282022-11-29 Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis Yang, Bing Parker, Robert B. Meibohm, Bernd Temrikar, Zaid H. Srivastava, Ashish Laizure, S. Casey PLoS One Research Article Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous esterases in the intestines and other tissues, but the specific enzymes involved are unknown. We hypothesized based on its structure and extensive presystemic metabolism that DMF would be a carboxylesterase substrate subject to interaction with alcohol. We sought to determine the enzymes(s) responsible for the extensive presystemic metabolism of DMF to MMF and the effect of alcohol on its disposition by conducting metabolic incubation studies in human recombinant carboxylesterase-1 (CES1), carboxylesterase-2 (CES2) and human intestinal microsomes (HIM), and by performing a follow-up study in an in vivo mouse model. The in vitro incubation studies demonstrated that DMF was only metabolized to MMF by CES1. Consistent with the incubation studies, the mouse pharmacokinetic study demonstrated that alcohol decreased the maximum concentration and area-under-the-curve of MMF in the plasma and the brain after dosing with DMF. We conclude that alcohol may markedly decrease exposure to the active MMF metabolite in the plasma and brain potentially decreasing the effectiveness of DMF in the treatment of RRMS. Public Library of Science 2022-11-28 /pmc/articles/PMC9704628/ /pubmed/36441753 http://dx.doi.org/10.1371/journal.pone.0278111 Text en © 2022 Yang et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yang, Bing
Parker, Robert B.
Meibohm, Bernd
Temrikar, Zaid H.
Srivastava, Ashish
Laizure, S. Casey
Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
title Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
title_full Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
title_fullStr Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
title_full_unstemmed Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
title_short Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
title_sort alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704628/
https://www.ncbi.nlm.nih.gov/pubmed/36441753
http://dx.doi.org/10.1371/journal.pone.0278111
work_keys_str_mv AT yangbing alcoholinhibitsthemetabolismofdimethylfumaratetotheactivemetaboliteresponsiblefordecreasingrelapsefrequencyinthetreatmentofmultiplesclerosis
AT parkerrobertb alcoholinhibitsthemetabolismofdimethylfumaratetotheactivemetaboliteresponsiblefordecreasingrelapsefrequencyinthetreatmentofmultiplesclerosis
AT meibohmbernd alcoholinhibitsthemetabolismofdimethylfumaratetotheactivemetaboliteresponsiblefordecreasingrelapsefrequencyinthetreatmentofmultiplesclerosis
AT temrikarzaidh alcoholinhibitsthemetabolismofdimethylfumaratetotheactivemetaboliteresponsiblefordecreasingrelapsefrequencyinthetreatmentofmultiplesclerosis
AT srivastavaashish alcoholinhibitsthemetabolismofdimethylfumaratetotheactivemetaboliteresponsiblefordecreasingrelapsefrequencyinthetreatmentofmultiplesclerosis
AT laizurescasey alcoholinhibitsthemetabolismofdimethylfumaratetotheactivemetaboliteresponsiblefordecreasingrelapsefrequencyinthetreatmentofmultiplesclerosis