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Detection of fumarate–glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism

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Abstract

Dimethylfumarate (DMF), the essential ingredient of the drug product Fumaderm®, is used to treat psoriasis with a recognized favorable long-term safety profile. Interestingly, the mode of action and the pharmacokinetics of DMF in psoriasis or multiple sclerosis are not fully explored. It is known that DMF as an α,β-unsaturated carboxylic acid ester forms an adduct with the antioxidant glutathione in vitro via a Michael-type addition within a very short period of time. In addition, it was shown that this reaction also takes place in vivo since the mercapturic acid of DMF was detected in urine of psoriasis patients after oral intake of Fumaderm®. To verify the hypothesis that DMF reacts with GSH already in or even before entering the portal vein blood an in vivo study in rats was initiated and portal vein blood was analyzed for the presence of DMF, MMF, GS-DMS and break down products, after DMF was given directly into the small intestine. The results show that no free DMF could be detected in the rat portal vein blood at any time point. MMF was the dominant metabolite and GS-DMS was also detectable in portal vein blood. In the rat mucosa the glutathione adducts of DMF and MMF were present. The data obtained provide evidence that the modulation of immune-mediated inflammatory pathways responsible for development of psoriasis and MS are targeted by DMF regulating redox-sensitive pathways for which the reaction with glutathione by DMF plays a crucial role.

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Abbreviations

DMF:

Dimethylfumarate

MMF:

Monomethylfumarate

FAE:

Fumaric acid esters

GSH:

Glutathione

GS-DMS:

S-(1,2-dimethoxycarbonylethyl)glutathione

GS-MMS:

Mixture of S-(1-carboxy-2-methoxycarbonylethyl)glutathione and S-(2-carboxy-1-methoxycarbonylethyl)glutathione

N-Gly-DMS:

S-(1,2-dimethoxycarbonylethyl)cysteinylglycine

N-Gly-MMS:

Mixture of S-(1-carboxy-2-methoxycarbonylethyl)cysteinylglycine and S-(2-carboxy-1-methoxycarbonylethyl)cysteinylglycine

N-DMS:

S-(1,2-dimethoxycarbonylethyl)cysteine

N-MMS:

Mixture of S-(1-carboxy-2-methoxycarbonylethyl)cysteine and S-(2-carboxy-1-methoxycarbonylethyl)cysteine

NAC-DMS:

N-acetyl-S-(1,2-dimethoxycarbonylethyl)cysteine

NAC-MMS:

Mixture of N-acetyl-S-(1-carboxy-2-methoxycarbonylethyl)cysteine and N-acetyl-S-(2-carboxy-1-methoxycarbonylethyl)cysteine

KEAP-1:

Kelch-like ECH-associated protein 1

Nrf2:

Nuclear-factor (erythroid-derived 2)-related factor-2

VEGFR2:

Vascular endothelial growth factor receptor

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Acknowledgments

We would like to thank Lisa Philipp for skilful technical assistance.

Conflict of interest

MRY and UM received educational grants and served as speakers and advisors for Biogen Idec, the manufacturer of the registered drug product Fumaderm®. TSN is an employee of LEO Pharma A/S, Ballerup, Denmark. All other authors declare no conflict of interest.

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Authors and Affiliations

  1. Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

    Stefan Dibbert, Ulrich Mrowietz & Martin Rostami-Yazdi

  2. Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, University of Kiel, Kiel, Germany

    Bernd Clement

  3. Department of Molecular Biomedicine, LEO Pharma A/S, Ballerup, Denmark

    Tine Skak-Nielsen

  4. Department of Dermatology, University of Kiel, Schittenhelmstr. 7, 24105, Kiel, Germany

    Martin Rostami-Yazdi

Authors
  1. Stefan Dibbert
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  2. Bernd Clement
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  3. Tine Skak-Nielsen
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  4. Ulrich Mrowietz
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  5. Martin Rostami-Yazdi
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Corresponding author

Correspondence to Martin Rostami-Yazdi.

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Dibbert, S., Clement, B., Skak-Nielsen, T. et al. Detection of fumarate–glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism. Arch Dermatol Res 305, 447–451 (2013). https://doi.org/10.1007/s00403-013-1332-y

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  • DOI: https://doi.org/10.1007/s00403-013-1332-y

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