Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole

Electrophysiologic Effects of Astemizole Metabolites. Introduction: The sel ective H-1-receptor antagonist astemizole (Hismanal) causes acquired long Q T syndrome, Astemizole blocks the rapidly activating delayed rectifier K+ c urrent I-Kr and the human ether-a go-go related gene (HERG) K+ channels tha t underlie it. Astemizole also is rapidly metabolized. The principal metabo lite is desmethylastemizole, which retains H-1-receptor antagonist properti es, 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 me tabolite is norastemizole, which appears in serum in low concentrations fol lowing astemizole ingestion and has undergone development as a new antihist amine drug. Our objective in the present work,vas to study the effects of d esmethylastemizole, norastemizole, and astemizole on HERO 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 depen dent. Norastemizole also blocked HERG current; however, block was incomplet e and required higher drug concentrations (half-maximal block of 27.7 nM). Conclusions: Desmethylastemizole and astemizole cause equipotent block of H ERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in s erum, these findings support the postulate that it becomes the principal ca use of long QT syndrome observed in patients following astemizole ingestion . Norastemizole block of HERG channels is weaker; thus, the risk of produci ng ventricular arrhythmias may be lower. These findings underscore the pote ntial roles of some H-1-receptor antagonist metabolites as K+ channel antag onists.