Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolimod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation

• Published in: Toxicology and applied pharmacology Vol. 281; no. 1; pp. 39 - 47
• Main Authors: Yagi, Yukihiro, Nakamura, Yuji, Kitahara, Ken, Harada, Takuma, Kato, Kazuhiko, Ninomiya, Tomohisa, Cao, Xin, Ohara, Hiroshi, Izumi-Nakaseko, Hiroko, Suzuki, Kokichi, Ando, Kentaro, Sugiyama, Atsushi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.11.2014; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ACETYLCHOLINE; Animals; Atrioventricular Block - chemically induced; Atrioventricular Block - physiopathology; Atrioventricular conduction block; Biological and medical sciences; BRAIN; Brugada Syndrome - chemically induced; Brugada Syndrome - physiopathology; Cardiac Conduction System Disease; Cardiac dysrhythmias; Cardiology. Vascular system; COMPARATIVE EVALUATIONS; DOSES; ELECTROCARDIOGRAMS; ETHERS; Fingolimod; Fingolimod Hydrochloride - metabolism; Fingolimod Hydrochloride - toxicity; GENES; GTP-ASES; Guinea pig; GUINEA PIGS; HEART; Heart Conduction System - drug effects; Heart Conduction System - physiopathology; HEK293 Cells; Humans; Immunosuppressive Agents - toxicity; IN VITRO; IN VIVO; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Male; Medical sciences; PHOSPHATES; QT-interval prolongation; RECEPTORS; Receptors, Lysosphingolipid - metabolism; Receptors, Lysosphingolipid - physiology; Siponimod; Sphingosine 1-phosphate; Toxicology; ERP; FDA; ERP(CL250); DMSO; fingolimod-P; Ito; Atrioventricular conduction block; MAP90; MAP90(CL300); ERP(CL200); Sphingosine 1-phosphate; QT-interval prolongation; S1P; Guinea pig; ANOVA; GIRK/IKACh; hERG; Fingolimod; MAP90(CL250); ECG; MAP90(CL200); ERP(CL300); ICH; MAP90(sinus); Siponimod; MAP; Ki; Arrhythmia; Atrioventricular bloc; Cardiovascular disease; Age of onset; Heart block; Heart disease; Sphingosine-1-phosphate; Conduction block; Mechanism of action; QT interval; Sphingosine 1-phosphate receptor; Modulator; Rodentia; Prolonged QT interval; Conduction disorder; Immunomodulator; Vertebrata; Mammalia; Animal; Immunosuppressive agent
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.09.006

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. •Fingolimod and siponimod are S1P1,3,4,5 and S1P1,5 receptor modulators, respectively.•Fingolimod and siponimod induced AV block in the halothane-anesthetized guinea pigs.•S1P1 in the hearts may be the target of fingolimod- and siponimod-induced AV block.•Fingolimod directly inhibited hERG current, which was not observed by siponimod.•IKr inhibition may play a key role in the fingolimod-induced QT prolongation.