Author + information
- Received April 24, 1996
- Revision received July 8, 1996
- Accepted July 12, 1996
- Published online November 15, 1996.
- Vicken R. Vorperian, MD, FACC,
- Zhengfeng Zhou, MD, PhD,
- Saeed Mohammad, MD,
- Timothy J. Hoon, PharmD,
- Christian Studenik, PhD, FACC and
- Craig T. January, FACC∗
- ↵∗Address for correspondence: Dr. Craig T. January, Section of Cardiology, Room H6/352 CSC, University of Wisconsin Hospitals and Clinics, 600 Highland Avenue, Madison, Wisconsin 53792.
Objectives. Proarrhythmic effects have been observed with the selective histamine1 (H1) receptor antagonist drug astemizole, a widely prescribed antihistamine. The metabolites of astemizole and those of other antihistamine compounds have not been implicated as causative agents of cardiac arrhythmias. The purpose of this study was to examine whether desmethylastemizole, the principal metabolite of astemizole, blocks delayed rectifier potassium (K+) channels.
Background. QT interval prolongation and torsade de pointes are associated with astemizole intake and have been ascribed to block the repolarizing K+ currents, specifically the rapidly activating component of the delayed rectifier iKr. Astemizole undergoes extensive first-pass metabolism, and its dominant metabolite, desmethylastemizole, has a markedly prolonged elimination time. We report the clinical observation of QT prolongation and torsade de pointes in a patient with undetectable serum concentrations of astemizole (<0.5 ng/ml) and “therapeutic” concentrations of desmethylastemizole (up to 7.7 ng/ml or 17.3 nmol/liter).
Methods. The perforated patch clamp recording technique was used to study the effects of desmethylastemizole (20 nmol/liter) on action potentials and iKr in isolated rabbit ventricular myocytes.
Results. Desmethylastemizole produced action potential prolongation and the induction of plateau early afterdepolarizations. Under voltage clamp conditions, desmethylastemizole suppressed iKr amplitude by ≈65%. The drug E-4031 (100 nmol/liter), which selectively blocks iKr, had a similar effect on current amplitude.
Conclusions. Desmethylastemizole, the major astemizole metabolite, blocks the repolarizing K+ current iKr with high affinity. The clinical observation of QT prolongation and torsade de pointes found with astemizole intake may principally be caused by the proarrhythmic effects of its metabolite desmethylastemizole.
☆ This study was supported in part by Grant HL 38927 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland and by the Oscar Rennenbohm Foundation, Madison, Wisconsin.
- Received April 24, 1996.
- Revision received July 8, 1996.
- Accepted July 12, 1996.