New and Old Horizons for an Ancient Drug: Pharmacokinetics, Pharmacodynamics, and Clinical Perspectives of Dimethyl Fumarate

Abstract

(1) Background: In their 60-year history, dimethyl fumarate and other salts of fumaric acid have been used for the treatment of psoriasis and other immune-mediated diseases for their immune-modulating properties. Over the years, new mechanisms of action have been discovered for this evergreen drug that remains a first-line treatment for several different inflammatory diseases. Due to its pleiotropic effects, this molecule is still of great interest in varied conditions, not exclusively inflammatory diseases. (2) Methods: The PubMed database was searched using combinations of the following keywords: dimethyl fumarate, pharmacokinetics, pharmacodynamics, adverse effects, psoriasis, multiple sclerosis, and clinical indications. This article reviews and updates the pharmacokinetics, mechanisms of action, and clinical indications of dimethyl fumarate. (3) Conclusions: The pharmacology of dimethyl fumarate is complex, fascinating, and not fully known. Progressive insights into the molecule's mechanisms of action will make it possible to maximize its clinical efficacy, reduce concerns about adverse effects, and find other possible areas of application.

Keywords: adverse effects; dimethyl fumarate; immune-mediated diseases; multiple sclerosis; pharmacodynamics; pharmacokinetics; psoriasis.

Figure 1

Pre-systemic metabolism of dimethyl fumarate to monomethyl fumarate by esterase.

Figure 2

Effect of dimethyl fumarate on Nrf2 pathway. Abbreviations: NRF2, nuclear factor (erythroid-derived 2)-related factor; ARE, antioxidant response element; CUL3, Cullin3; KEAP1, Kelch-like ECH-associated protein; PKC, protein kinase C; Ub, ubiquitin; ROS, reactive oxygen species.