CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis.

Article Details

Citation Copy to clipboard

Jin Y, Zollinger M, Borell H, Zimmerlin A, Patten CJ

CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis.

Drug Metab Dispos. 2011 Feb;39(2):191-8. doi: 10.1124/dmd.110.035378. Epub 2010 Nov 2.

PubMed ID

21045201 [ View in PubMed

]

Abstract

Fingolimod (FTY720, Gilenya, 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol) is a novel drug recently approved in the United States for the oral treatment of relapsing multiple sclerosis. The compound is eliminated predominantly by omega-hydroxylation, followed by further oxidation. The omega-hydroxylation was the major metabolic pathway in human liver microsomes (HLM). The enzyme kinetics in HLM were characterized by a Michaelis-Menten affinity constant (K(m)) of 183 muM and a maximum velocity (V(max)) 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 (P450) enzymes or of flavin-containing monooxygenase (FMO). Among 21 recombinant human P450 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 (K(i)) of 0.74 muM (and by recombinant CYP4F2 with an IC(50) of 1.6 muM), whereas there was only a slight inhibition found with azamulin and none with troleandomycin. An antibody against CYP4F2 was able to inhibit the metabolism of fingolimod almost completely 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 omega-hydroxylation of fingolimod, the main elimination pathway of the drug in vivo.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Fingolimod	Cytochrome P450 2E1	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Fingolimod Ketoconazole	The serum concentration of Fingolimod can be increased when it is combined with Ketoconazole.