# The Inhibition and Transesterification of Dimethyl Fumarate by Ethanol

> **NIH NIH R03** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $152,000

## Abstract

Project Summary
Dimethyl fumarate (DMF, Tecfidera™) is a first-line treatment for patients with relapsing forms
of multiple sclerosis that affects more than one million people in the U.S. DMF is a prodrug that
after oral administration undergoes complete presystemic metabolism to its active metabolite,
monomethyl fumarate (MMF). The metabolic pathway involved in conversion of DMF to MMF
remains uncertain, but our preliminary work shows that human carboxylesterase-1 (CES1), an
enzyme highly expressed in the liver, is primarily responsible. Furthermore, as has been shown
with other CES1 substrate drugs, DMF hydrolysis to MMF is inhibited by ethanol and it
undergoes transesterification with ethanol to form new ethylated metabolites of unknown
pharmacology. The overall objective in this application is to determine how ethanol affects DMF
metabolism and disposition in vitro and in vivo. The overall hypothesis is that ethanol will
decrease MMF active metabolite formation and produce the transesterification metabolite, ethyl
methyl fumarate. This hypothesis will be tested by pursuing two specific aims: (1) Identify the
DMF-ethanol transesterification product; and (2) determine the effect of ethanol on DMF
disposition in a mouse model. In the first aim, human recombinant CES1 will be used to
determine the effects of ethanol on DMF hydrolysis in vitro and to identify the transesterification
product. For the second aim, a novel plasma carboxylesterase-deficient mouse model will be
used to characterize how ethanol affects the in vivo disposition of DMF. This new knowledge will
provide important insight into the potential of ethanol to alter the safety and effectiveness of
DMF therapy in patients with multiple sclerosis. The impact of ethanol’s effects on DMF therapy
are highly relevant as ethanol has been reported to decrease the progression of disability in
patients with multiple sclerosis and the prevalence of ethanol consumption in patients with
multiple sclerosis is similar to the general population. Thus, the interaction between DMF and
ethanol will be a common occurrence in patients on chronic, lifelong DMF therapy, which could
alter the effectiveness of DMF in the treatment of their multiple sclerosis.

## Key facts

- **NIH application ID:** 9952704
- **Project number:** 1R03NS116229-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Steven Casey Laizure
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $152,000
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952704

## Citation

> US National Institutes of Health, RePORTER application 9952704, The Inhibition and Transesterification of Dimethyl Fumarate by Ethanol (1R03NS116229-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9952704. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*