Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole.
OBJECTIVE
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 approximately 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.
Vorperian
V R
VR
Department of Medicine, University of Wisconsin, Madison 53792, USA.
Zhou
Z
Z
Mohammad
S
S
Hoon
T J
TJ
Studenik
C
C
January
C T
CT
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016589:Astemizole / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006323:Heart Arrest / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D006634:Histamine H1 Antagonists / Q000097:blood; D006801:Humans; D015221:Potassium Channels / Q000187:drug effects*; D011817:Rabbits; D016171:Torsades de Pointes / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology
D006634:Histamine H1 Antagonists; D015221:Potassium Channels; D016589:Astemizole; C040463:desmethylastemizole