title: Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.
abstract: OBJECTIVE
  Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) could be used to identify pro-arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro-arrhythmic properties of I(Kr) blockers, using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds).
  
  
  METHODS
  Assays included the anaesthetized remodelled chronic complete AV block (CAVB) dog, the anaesthetized methoxamine-sensitized unremodelled rabbit, multi-cellular hESC-CM clusters, isolated CM obtained from CAVB dogs and isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models and early afterdepolarizations (EADs) in the cell models.
  
  
  RESULTS
  At clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (≥100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E-4031 induced EADs or TdP in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization.
  
  
  CONCLUSIONS
  Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide or E4031.
authors: Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: L
authors: L
authors: Nalos
authors: R
authors: R
authors: Varkevisser
authors: M K B
authors: MK
authors: Jonsson
authors: M J C
authors: MJ
authors: Houtman
authors: J D
authors: JD
authors: Beekman
authors: R
authors: R
authors: van der Nagel
authors: M B
authors: MB
authors: Thomsen
authors: G
authors: G
authors: Duker
authors: P
authors: P
authors: Sartipy
authors: T P
authors: TP
authors: de Boer
authors: M
authors: M
authors: Peschar
authors: M B
authors: MB
authors: Rook
authors: T A B
authors: TA
authors: van Veen
authors: M A G
authors: MA
authors: van der Heyden
authors: M A
authors: MA
authors: Vos
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006327:Heart Block / Q000503:physiopathology; D006801:Humans; D008729:Methoxamine; D000077266:Moxifloxacin; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D010627:Phenethylamines; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D011804:Quinolines; D013449:Sulfonamides; C063968:E 4031; D008729:Methoxamine; C063533:dofetilide; D000077266:Moxifloxacin