Torsades de pointes occurring in association with terfenadine use.

Torsades de pointes is a form of polymorphic ventricular tachycardia that is associated with prolongation of the QT interval. Although found in many clinical settings, torsades de pointes is most often drug induced. This report describes the first association (exclusive of drug overdose) of symptomatic torsades de pointes occurring with the use of terfenadine in a patient who was taking the recommended prescribed dose of this drug in addition to cefaclor, ketoconazole, and medroxyprogesterone. Measured serum concentrations of terfenadine and its main metabolite showed excessive levels of parent terfenadine and proportionately reduced concentrations of metabolite, suggesting inhibition of terfenadine metabolism. We believe that a drug interaction between terfenadine and ketoconazole resulted in the elevated terfenadine levels in plasma and in the cardiotoxicity previously seen only in cases of terfenadine overdose.

[1]  J. Ritter,et al.  Induction and inhibition of rat hepatic drug metabolism by N-substituted imidazole drugs. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[2]  D. Feldman,et al.  Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. , 1983, The Journal of clinical investigation.

[3]  M. Eichelbaum.  Polymorphism of drug oxidation in man: novel findings , 1981 .

[4]  K. Speeg,et al.  The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro. , 1985, Drug metabolism and disposition: the biological fate of chemicals.

[5]  V. Harindra,et al.  Cardiotoxic effect with convulsions in terfenadine overdose. , 1989, BMJ.

[6]  M. Brown,et al.  Effect of ketoconazole on hepatic oxidative drug metabolism , 1985, Clinical pharmacology and therapeutics.

[7]  S. Schenker,et al.  Inhibition of microsomal drug metabolism by histamine H2-receptor antagonists studied in vivo and in vitro in rodents , 1982 .

[8]  A. Bast,et al.  Inhibition of mono-oxygenase and oxidase activity of rat-hepatic cytochrome P-450 by H2-receptor blockers. , 1984, Xenobiotica; the fate of foreign compounds in biological systems.

[9]  R. Heel,et al.  Terfenadine , 2012, Drugs.

[10]  P. Beaune,et al.  Drug interactions with macrolide antibiotics: specificity of pseudo-suicide inhibition and induction of cytochrome P-450. , 1986, Advances in experimental medicine and biology.

[11]  E. Aliot,et al.  The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. , 1988, Progress in cardiovascular diseases.