title: Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolimod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation.
abstract: Fingolimod, a sphingosine 1-phosphate (S1P) receptor subtype 1, 3, 4 and 5 modulator, has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular conduction block and/or QT-interval prolongation have been reported in some patients after the first dose. In this study, we directly compared the electropharmacological profiles of fingolimod with those of siponimod, a modulator of sphingosine 1-phosphate receptor subtype 1 and 5, using in vivo guinea-pig model and in vitro human ether-a-go-go-related gene (hERG) assay to better understand the onset mechanisms of the clinically observed adverse events. Fingolimod (0.01 and 0.1mg/kg) or siponimod (0.001 and 0.01mg/kg) was intravenously infused over 10min to the halothane-anaesthetized guinea pigs (n=4), whereas the effects of fingolimod (1μmol/L) and siponimod (1μmol/L) on hERG current were examined (n=3). The high doses of fingolimod and siponimod induced atrioventricular conduction block, whereas the low dose of siponimod prolonged PR interval, which was not observed by that of fingolimod. The high dose of fingolimod prolonged QT interval, which was not observed by either dose of siponimod. Meanwhile, fingolimod significantly inhibited hERG current, which was not observed by siponimod. These results suggest that S1P receptor subtype 1 in the heart could be one of the candidates for fingolimod- and siponimod-induced atrioventricular conduction block since S1P receptor subtype 5 is localized at the brain, and that direct IKr inhibition may play a key role in fingolimod-induced QT-interval prolongation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa 222-8567, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yagi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kitahara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Harada
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa 222-8567, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kato
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa 222-8567, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Ninomiya
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa 222-8567, Japan.
authors.forename: Kokichi
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address: atsushi.sugiyama@med.toho-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D054537:Atrioventricular Block / Q000139:chemically induced* / Q000503:physiopathology; D053840:Brugada Syndrome / Q000139:chemically induced / Q000503:physiopathology; D000075224:Cardiac Conduction System Disease; D000068876:Fingolimod Hydrochloride / Q000378:metabolism* / Q000633:toxicity*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D049349:Receptors, Lysosphingolipid / Q000378:metabolism* / Q000502:physiology
chemical_list: D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride
keywords: Atrioventricular conduction block; Fingolimod; Guinea pig; QT-interval prolongation; Siponimod; Sphingosine 1-phosphate