title: Cardiotoxic and drug interaction profile of the second generation antihistamines ebastine and terfenadine in an experimental animal model of torsade de pointes.
abstract: Second generation antihistamines are widely used because of their efficacy in treating allergic disorders without significant sedative side effects. Recent clinical evidence shows that some of the early prototypes in this class, namely terfenadine and astemizole, have the potential for producing torsade de pointes, a rare form of ventricular arrhythmia that is life-threatening. Important questions have been raised as to whether this is a property shared by newer, recently-introduced second generation antihistamines. The objective of this study was to characterize and compare the ECG and cardiovascular effects of terfenadine (CAS 50679-08-8) and ebastine (CAS 90729-43-4), a new second generation antihistamine, in an experimental animal model predictive of the cardiotoxic proclivity of these agents. Also, the drug interaction effect of the antifungal drug ketoconazole (CAS 65277-42-1) was evaluated, which blocks hepatic first-pass biotransformation of ebastine and terfenadine leading to increased cardiotoxity of terfenadine in man, on the ECG effects of terfenadine and ebastine in this animal model. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) were administered intravenously to anesthetized guinea pigs. Electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured during the course of the experiment. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. In separate studies in conscious guinea pigs, the effect of oral ketoconazole (200 mg) on the ECG effects of oral terfenadine (60 mg) and ebastine (10 mg) was studied. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) produced significant prolongation of the QTc interval and disruption of the ECG signal when given intravenously to anesthetized guinea pigs. The ECG effects were characterized by large amplitude, morphologically aberrant T-waves, and instances of arrhythmogenic activity. Both drugs produced pronounced bradycardia and hypotension. In conscious animals, pretreatment with oral ketoconazole significantly enhanced the QTc interval prolongation effects of terfenadine and ebastine. Oral terfenadine and ebastine, when given alone at the doses tested, were devoid of adverse QTc interval prolongation effects in the conscious guinea pig. In separate studies in conscious guinea pigs, oral loratadine (10 mg; CAS 79794-75-5) given alone or in animals pretreated with ketoconazole did not affect ECG parameters. The present studies show that terfenadine and ebastine share similar cardiotoxic properties characterized by QTc interval prolongation, bradycardia, hypotension and proarrhythmogenic activity in the anesthetized guinea pig. In addition, pretreatment with ketoconazole enhances the QTc interval effect of both drugs, most likely due to the accumulation of parent compound that occurs after blockade of hepatic metabolism by CYP3A4. In conclusion, our findings indicate that ebastine and terfenadine display similarities in their inherent potential for cardiotoxic and adverse drug interaction effects. In contrast, loratadine is devoid of adverse ECG and drug interaction effects.
authors.affiliation: Schering-Plough Research Institute, Allergy, Kenilworth, New Jersey, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Hey
authors.forename: M
authors.initials: M
authors.lastname: del Prado
authors.forename: W
authors.initials: W
authors.lastname: Kreutner
authors.forename: R W
authors.initials: RW
authors.lastname: Egan
mesh_terms: D000818:Animals; D002090:Butyrophenones / Q000633:toxicity*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010880:Piperidines / Q000633:toxicity*; D016593:Terfenadine / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; C058249:ebastine