Validity of in vitro studies with fumaric acid esters for treatment situations in humans : a literature based analysis

Besides methotrexate, ciclosporin, hydroxycarbamide and retinoids, fumaric acid esters based drugs are used since 1971 as an immunosuppressive, respectively immunomodulatory, medication in the therapy of severe psoriasis. The latter substances are currently subject of great interest as an oral treatment for several autoimmune diseases including multiple sclerosis. During the past years, several pharmaceutical products containing dimethylfumarate as main active component of all licensed drugs have been released.

The exact mechanism of action of fumaric acid esters still remains an open problem. Recent studies demonstrate that dimethylfumarate have also a significant biological effect in vitro. However, the pharmacokinetics and chemistry of dimethylfumarate and other fumaric acid esters are often not fully considered in the design and interpretation of the most experiments.

In this literature-based analysis the content from more than 300 articles dating from 1971 to 2022 were compared and validated. 

Based on this data it was discovered that monomethylfumarate has a higher biochemical impact than dimethylfumarate, because dimethylfumarate is a plasma-membrane permeable prodrug that in vivo rapidly converts to monomethylfumarate. This makes monomethylfumarate the main active compound of oral drugs and means that monomethylfumarate is the only substance to directly interact with the intracellular signaling pathways in vivo.

Recent works are often concentrated on the direct effects of dimethylfumarate on cells in vitro, which, having the metabolism of dimethylfumarate in mind will never be exposed to this particular fumaric acid ester in an actual human organism. This shows that, unfortunately, most of the performed in vitro studies are not valid for treatment situations in vivo.

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