Zf. Zhou et al., Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole, J CARD ELEC, 10(6), 1999, pp. 836-843
Citations number
30
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
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.