Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans?
The cardiac action potential results from a dynamic balance between inward depolarising Na+ and Ca2+ currents and outward K+ repolarising currents. During a cardiac cycle, the resultant of repolarisation phase from all ventricular cells is represented by the QT interval of the surface ECG. Congenital long QT syndrome (LQTS) is characterised by polymorphic ventricular tachycardia sometimes with twisting QRS morphology (torsade de pointes) which, although usually self-limiting, can result in sudden cardiac death. Acquired LQTS can be induced by a variety of drugs, including some nonsedative histamine H1 receptor antagonists (astemizole, terfenadine). The Committee for Proprietary Medicinal Products of the European Union has recently proposed studying the action potential in in vitro heart preparations as a preclinical test for predicting the propensity of noncardiovascular drugs to induce malignant QT prolongation in humans. The effects of several histamine H1 receptor antagonists on the electrically evoked action potential have been evaluated in rabbit Purkinje fibres. In this preparation, astemizole (0.3 to 10 micromol/L) prolongs the duration of the action potential measured at the level where repolarisation is 90% complete (APD90). This effect is dependent on drug concentration, incubation time, pacing frequency and K+ or Mg2+ concentration. Astemizole also markedly depresses the rate of rise of the action potential (Vmax). Terfenadine showed qualitatively similar, but quantitatively smaller, effects in this model. The histamine H1 receptor antagonists cetirizine, ebastine, carebastine, loratadine and fexofenadine do not significantly affect APD90 at 1 micromol/L, but cetirizine and carebastine prolong it slightly at 10 micromol/L. In conclusion, in rabbit Purkinje fibres, astemizole and terfenadine produce adverse electrophysiological effects at concentrations which may be achieved in the human myocardium in certain clinical situations. APD90 lengthening induced by carebastine and cetirizine is minor and occurs at concentrations that are very unlikely to be encountered clinically, since these drugs, in contrast to astemizole and terfenadine, do not accumulate in the myocardium. Direct extrapolation of preclinical results to humans requires great caution, since malignant QT prolongations by terfenadine and astemizole are extremely rare clinical events. However, since prolongation of the QT interval often precedes the development of torsade de pointes, any significant delay in cardiac repolarisation produced by noncardiovascular drugs in preclinical, and particularly in clinical, studies should, in general, be considered to indicate a potential cardiac risk in humans. Its significance should subsequently be evaluated in appropriate studies in patients with conditions known to predispose to arrhythmias.
Cavero
I
I
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Mestre
M
M
Guillon
J M
JM
Heuillet
E
E
Roach
A G
AG
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006634:Histamine H1 Antagonists / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D011237:Predictive Value of Tests
D006634:Histamine H1 Antagonists