Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways

Delayed–release dimethyl fumarate (DMF), Tecfidera^®, is approved globally for treating relapsing-remitting multiple sclerosis. The disposition of DMF was determined in humans after administration of a single oral dose of [¹⁴C]DMF, and the total recovery was estimated to be between 58.4% to 75.0%, primarily through expired air.The absorption of [¹⁴C]DMF-derived radioactivity was rapid, with Tmax at 1h postdose. Glucose was the predominant circulating metabolite, accounting for ∼60% of the total extractable radioactivity. Cysteine and N-acetylcysteine conjugates of mono- or di-methyl succinate were found to be the major urinary metabolites.In vitro studies showed that [¹⁴C]DMF was mainly metabolised to MMF, and fumarase exclusively converted fumaric acid to malic acid and did not catalyse the conversion of fumaric acid esters to malic acid. DMF was observed to bind with human serum albumin through Michael addition to the Cys-34 residue when exposed to human plasma.These findings indicate that DMF undergoes metabolism via hydrolysis, GSH conjugation, and the TCA cycle, leading to the formation of citric acid, CO₂, and water. These ubiquitous and well-conserved metabolism pathways minimise the risk of drug-drug interactions and reduce variability related to pharmacogenetics and ethnicity. Delayed–release dimethyl fumarate (DMF), Tecfidera^®, is approved globally for treating relapsing-remitting multiple sclerosis. The disposition of DMF was determined in humans after administration of a single oral dose of [¹⁴C]DMF, and the total recovery was estimated to be between 58.4% to 75.0%, primarily through expired air. The absorption of [¹⁴C]DMF-derived radioactivity was rapid, with Tmax at 1h postdose. Glucose was the predominant circulating metabolite, accounting for ∼60% of the total extractable radioactivity. Cysteine and N-acetylcysteine conjugates of mono- or di-methyl succinate were found to be the major urinary metabolites. In vitro studies showed that [¹⁴C]DMF was mainly metabolised to MMF, and fumarase exclusively converted fumaric acid to malic acid and did not catalyse the conversion of fumaric acid esters to malic acid. DMF was observed to bind with human serum albumin through Michael addition to the Cys-34 residue when exposed to human plasma. These findings indicate that DMF undergoes metabolism via hydrolysis, GSH conjugation, and the TCA cycle, leading to the formation of citric acid, CO₂, and water. These ubiquitous and well-conserved metabolism pathways minimise the risk of drug-drug interactions and reduce variability related to pharmacogenetics and ethnicity.