This work was supported in part by the Oscar Rennebohm Foundation, an American Heart Association Scientist Development Grant (Dr. Zhou), and a Fellowship Grant from the Wisconsin Affiliate of the American Heart Association (Dr. Zhang).
Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole
Version of Record online: 20 APR 2007
Journal of Cardiovascular Electrophysiology
Volume 10, Issue 6, pages 836–843, June 1999
How to Cite
ZHOU, Z., VORPERIAN, V. R., GONG, Q., ZHANG, S. and JANUARY, C. T. (1999), Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole. Journal of Cardiovascular Electrophysiology, 10: 836–843. doi: 10.1111/j.1540-8167.1999.tb00264.x
- Issue online: 20 APR 2007
- Version of Record online: 20 APR 2007
- Manuscript received 10 December 1998; Accepted for publication 24 February 1999.
- potassium channels;
- IKr arrhythmia;
- long QT syndrome;
Electrophysiologic Effects of Astemizole Metabolites. Introduction: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current IKr and the human ether-a go-go-related gene (HKRG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1-receptor antagonist properties, has a long elimination time of 9 to 13 days, and its steady-state serum concentration exceeds that of astemizole by more than 30-fold. A second metabolite is norastemizole, which appears in serum in low concentrations following astemizole ingestion and has undergone development as a new antihistamine drug. Our objective in the present work was to study the effects of desmethylastemizole, norastemizole, and astemizole on HERG K+ channels.
Methods and Results: HERG channels were expressed in a mammalian (HEK 293) cell line and studied using the patch clamp technique. Desmethylastemizole and astemizole blocked HERG current with similar concentration dependence (half-maximal block of 1.0 and 0.9 nM, respectively) and block was use dependent. Norastemizole also blocked HERG current; however, block was incomplete and required higher drug concentrations (half-maximal block of 27.7 nM).
Conclusions: Desmethylastemizole and astemizole cause equipotent block of HERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists.