Ethanol Inhibits the Metabolism of the Multiple Sclerosis Drug Dimethyl Fumarate to its Active Metabolite and Decreases Brain Exposure

Abstract

HypothesisDimethyl fumarate is primarily metabolized to the monomethyl fumarate active metabolite by carboxylesterase 1 and is subject to inhibition by ethanol.MethodsA pharmacokinetic study was conducted to determine the effect of ethanol on dimethyl fumarate disposition in ES1e mice, a strain that is a better model of human carboxylesterase drug metabolism than typical rodent strains. The disposition of dimethyl fumarate and monomethyl fumarate, the purported active metabolite, was determined in a control group (n=30) receiving 100 mg/kg of dimethyl fumarate via oral gavage versus an ethanol group (n=30) receiving 3 g/kg of ethanol by oral gavage 10 minutes prior to dosing with 100 mg/kg of dimethyl fumarate. The area‐under‐the‐curve (AUC) and maximum plasma concentration (Cmax) were determined in plasma and brain tissue from the drug and metabolite concentrations determined by LC‐ mass spectrometry. The AUC and Cmax were compared between the control and ethanol group.ResultsLike dimethyl fumarate disposition in humans, only monomethyl fumarate concentrations were quantifiable in the plasma in the control group. In the ethanol group, dimethyl fumarate was quantifiable in both the plasma and brain tissue. Control Ethanol DMF MMF DMF MMF AUCPLASMA(ng/ml*min) ND 6072 4629 3948 CmaxPLASMA(ng/ml) ND 210 64 65 AUCBRAIN (ng/ml*min) ND 980 20 787 DMF=dimethyl fumarate; MMF=monomethyl fumarate (active metabolite); ND=not detectedThe terminal elimination half‐life of monomethyl fumarate in the control and ethanol groups was 14.4 and 44.3 minutes, respectively.ConclusionsEthanol inhibits the hydrolysis of dimethyl fumarate to active monomethyl fumarate by carboxylesterase 1 and has a drastic effect on the disposition of dimethyl fumarate and monomethyl fumarate. The therapeutic effect of dimethyl fumarate is likely to be significantly altered by the consumption of ethanol or other drug that inhibits carboxylesterase 1 potentially altering the beneficial effect of chronic dimethyl fumarate therapy on Relapsing‐Remitting Multiple Sclerosis.