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Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application

Schröder, Matthias ; Arlt, Olga ; Schmidt, Helmut ; Huwiler, Andrea ; Angioni, Carlo ; Pfeilschifter, Josef M. ; Schwiebs, Anja ; Radeke, Heinfried H.

In: Biological Chemistry, 2015, vol. 396, no. 6-7, p. 795-802

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    Titre
    • Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application
    Auteur
    • Schröder, Matthias. BioMed X Innovation Center, Im Neuenheimer Feld 583, 69120 Heidelberg, Germany
    • Arlt, Olga. Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Goethe University Frankfurt, Building 75, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
    • Schmidt, Helmut. Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University, D-60590 Frankfurt/Main, Germany
    • Huwiler, Andrea. Institute of Pharmacology, University of Bern, CH-3012 Bern, Switzerland
    • Angioni, Carlo. Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University, D-60590 Frankfurt/Main, Germany
    • Pfeilschifter, Josef M.. Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Goethe University Frankfurt, Building 75, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
    • Schwiebs, Anja. Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Goethe University Frankfurt, Building 75, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
    • Radeke, Heinfried H.. Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Goethe University Frankfurt, Building 75, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Biological Chemistry, 2015, vol. 396, no. 6-7, p. 795-802. De Gruyter
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:326501
    Summary
    FTY720 (Fingolimod; Gilenya®) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates.