Does terfenadine-induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes?
OBJECTIVE
Terfenadine has been reported to cause cardiac death. Hence, we investigated its pro-arrhythmic potential in various in vitro models.


METHODS
Pro-arrhythmic effects of terfenadine were investigated in rabbit isolated hearts and left ventricular wedge preparations. Also, using whole-cell patch-clamp recording, we examined its effect on the human ether-à-go-go-related gene (hERG) current in HEK293 cells transfected with hERG and on the I(Na) current in rabbit ventricular cells and human atrial myocytes.


RESULTS
Terfenadine concentration- and use-dependently inhibited I(Na) in rabbit myocytes and in human atrial myocytes and also inhibited the hERG. In both the rabbit left ventricular wedge and heart preparations, terfenadine at 1 µM only slightly prolonged the QT- and JT-intervals but at 10 µM, it caused a marked widening of the QRS complex, cardiac wavelength shortening, incidences of in-excitability and non-TdP-like ventricular tachycardia/fibrillation (VT/VF) without prolongation of the QT/JT-interval. At 10 µM terfenadine elicited a lower incidence of early afterdepolarizations versus non- Torsades de Pointes (TdP)-like VT/VF (100% incidence), and did not induce TdPs. Although the concentration of terfenadine in the tissue-bath was low, it accumulated within the heart tissue.


CONCLUSIONS
Our data suggest that: (i) the induction of non-TdP-like VT/VF, which is caused by slowing of conduction via blockade of I(Na) (like Class Ic flecainide), may constitute a more important risk for terfenadine-induced cardiac death; (ii) although terfenadine is a potent hERG blocker, the risk for non-TdP-like VT/VF exceeds the risk for TdPs; and (iii) cardiac wavelength (λ) could serve as a biomarker to predict terfenadine-induced VT/VF.
Center of Excellence for Cardiovascular Safety Research and Mechanistic Pharmacology, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium. hlu@its.jnj.com
Hua Rong
HR
Lu
An N
AN
Hermans
David J
DJ
Gallacher
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D020517:Atrial Appendage / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039563:Histamine H1 Antagonists, Non-Sedating / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009994:Osmolar Concentration; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000209:etiology*; D016593:Terfenadine / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000209:etiology*
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D039563:Histamine H1 Antagonists, Non-Sedating; D011994:Recombinant Proteins; D026941:Sodium Channel Blockers; D016593:Terfenadine