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CYP4F Enzymes are Responsible for the Elimination of Fingolimod (FTY720), a Novel Treatment of Relapsing Multiple Sclerosis

Jin, Yi, Zollinger, Markus, Borell, Hubert, Zimmerlin, Alfred Gilbert and Patten, Christopher (2011) CYP4F Enzymes are Responsible for the Elimination of Fingolimod (FTY720), a Novel Treatment of Relapsing Multiple Sclerosis. Drug Metabolism and Disposition, 39 (2). pp. 191-198. ISSN 1521-009X


Fingolimod is a novel drug in clinical development for the oral treatment of relapsing multiple sclerosis. The compound is eliminated predominantly by ω-hydroxylation, followed by further oxidation. The ω-hydroxylation was the major metabolic pathway in human liver microsomes (HLM). The enzyme kinetics in HLM were characterized by a Michaelis-Menten affinity constant (Km) of 183 µM and a maximum velocity (Vmax) of 1847 pmol/min/mg. Rates of fingolimod metabolism by a panel of HLM from individual donors showed no correlation with marker activities of any of the major drug metabolizing cytochrome P450 (CYP) enzymes or of flavin-containing monooxygenase (FMO). Among 21 recombinant human CYP enzymes and FMO3, only CYP4F2 (and to some extent CYP4F3B) produced metabolite profiles similar to those in HLM. Ketoconazole, known to inhibit not only CYP3A but also CYP4F2, was an inhibitor of fingolimod metabolism in HLM with an inhibition constant (Ki) of 0.74 µM (and by recombinant CYP4F2 with IC50 of 1.6 µM), while there was only a slight inhibition found with azamulin and none with troleandomycin. An antibody against CYP4F2 was able to inhibit almost completely the metabolism of fingolimod in HLM whereas antibodies specific to CYP2D6, CYP2E1, and CYP3A4 did not show significant inhibition. Combining the results of these four enzyme phenotyping approaches, we demonstrated that CYP4F2, and possibly other enzymes of the CYP4F subfamily (e.g., CYP4F3B), are the major enzymes responsible for the ω-hydroxylation of fingolimod, the main elimination pathway of the drug in vivo.

Item Type: Article
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Keywords: CYP4F2; CYP4F enzymes; fingolimod metabolism and elimination; FTY720; ketoconazole; Ki and IC50 values; enzyme phenotyping
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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