Effect of DMF and MEF on gene expression in select mouse organs: Single-dosing regimen

Delayed-release dimethyl fumarate (DMF) is approved in the United States, European Union, Canada, and Australia for the treatment of multiple sclerosis. DMF is also a component in a defined-mixture product with three salts of monoethyl fumarate (MEF) that is approved in Germany for the treatment of psoriasis. Characterizing common or distinct pharmacodynamic properties of DMF and MEF would provide insights into the mechanisms of action of delayed-release DMF versus fixed combination products containing DMF and MEF salts. In this study we evaluated the pharmacodynamic effects and pharmacokinetics of DMF and MEF in central nervous system and peripheral tissues of naïve mice following a single dose or 10 daily doses of DMF, MEF, or a combination of the two. DMF and MEF exhibited similar pharmacokinetic profiles, but differences were noted in biodistribution: monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited a higher degree of brain penetration, whereas MEF was preferentially partitioned into kidney. Both common and distinct pharmacodynamic responses were observed in all assessed tissues for DMF and MEF alone or in combination. These findings indicate that all fumaric acid esters cannot be considered equivalent, and combinations of compounds may exert effects not observed when agents are used individually. C57BL/6 mice were administered vehicle (0.8% hydroxypropyl methylcellulose), DMF (100 mg/kg or 179.2 mg/kg), a mixture of MEF salts (Ca2+, Mg2+, Zn2+; 79.2 mg/kg), or a combination of DMF (100 mg/kg) and MEF salts (79.2 mg/kg) as a single acute dose (n = 6−10 mice per dose group). Global transcriptional profiling was performed on whole blood and a panel of tissues (brain, inguinal lymph node, mesenteric lymph node, jejunum and spleen) to identify genes that were significantly modulated relative to vehicle controls 6 and 12 hours after the single dose.