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 (2015). Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application. Biological chemistry, 396(6-7), pp. 795-802. De Gruyter 10.1515/hsz-2014-0287

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1431-6730

Publisher:

De Gruyter

Language:

English

Submitter:

Debora Scherrer

Date Deposited:

23 Feb 2016 15:27

Last Modified:

03 Mar 2021 09:11

Publisher DOI:

10.1515/hsz-2014-0287

PubMed ID:

25720062

BORIS DOI:

10.7892/boris.76764

URI:

https://boris.unibe.ch/id/eprint/76764

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