Dimethyl Fumarate vs. Monomethyl Fumarate: Unresolved Pharmacologic Issues.

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Dimethyl fumarate (DMF) is approved for multiple sclerosis and psoriasis and is being explored for other non-malignant diseases.
• Despite extensive research, the active metabolite of DMF (DMF or monomethyl fumarate, MMF) and its metabolic pathways remain debated.
• Discrepancies exist between in vitro and in vivo findings regarding DMF's effects, potentially due to differing metabolic contributions.

Purpose of the Study:

• To review and highlight unresolved issues in the metabolism and pharmacology of dimethyl fumarate (DMF).
• To clarify the roles of DMF and its metabolite MMF in observed therapeutic and side effects.
• To address the complexities in translating preclinical findings to clinical practice.

Main Methods:

• Literature review of preclinical and clinical studies on dimethyl fumarate (DMF) metabolism.
• Analysis of enzymatic hydrolysis pathways, including carboxylesterases.
• Examination of the distinct and overlapping effects of DMF and MMF.

Main Results:

• The exact site, extent, and enzymes responsible for DMF hydrolysis to MMF are not fully elucidated and vary by tissue and species.
• The contribution of methanol, a co-product of DMF metabolism, to observed effects, including NRF2 activation, requires further investigation.
• Distinguishing the specific roles of DMF versus MMF in therapeutic actions and side effects remains challenging.

Conclusions:

• Unresolved questions regarding DMF metabolism and the active metabolite complicate its clinical application and interpretation of research findings.
• Further research is needed to clarify the precise metabolic fate of DMF and the specific contributions of DMF, MMF, and methanol to its overall effects.
• Addressing these pharmacological uncertainties is crucial for optimizing the use of DMF in current and potential future therapeutic indications.