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

Zhengfeng Zhou, Vicken R. Vorperian, Qiuming Gong, Shetuan Zhang, Craig T. January

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Introduction: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go- related gene (HERG) 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.

Original languageEnglish (US)
Pages (from-to)836-843
Number of pages8
JournalJournal of Cardiovascular Electrophysiology
Volume10
Issue number6
StatePublished - 1999
Externally publishedYes

Fingerprint

Astemizole
Histamine Antagonists
Potassium Channels
Ether
Genes
Histamine H1 Receptors
Long QT Syndrome
Eating
Serum
desmethylastemizole
tecastemizole
HEK293 Cells
Patch-Clamp Techniques
Pharmaceutical Preparations
Cardiac Arrhythmias

Keywords

  • Antihistamine
  • Arrhythmia
  • I(Kr)
  • Long QT syndrome
  • Potassium channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology

Cite this

Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. / Zhou, Zhengfeng; Vorperian, Vicken R.; Gong, Qiuming; Zhang, Shetuan; January, Craig T.

In: Journal of Cardiovascular Electrophysiology, Vol. 10, No. 6, 1999, p. 836-843.

Research output: Contribution to journalArticle

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abstract = "Introduction: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go- related gene (HERG) 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.",
keywords = "Antihistamine, Arrhythmia, I(Kr), Long QT syndrome, Potassium channels",
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T1 - Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole

AU - Zhou, Zhengfeng

AU - Vorperian, Vicken R.

AU - Gong, Qiuming

AU - Zhang, Shetuan

AU - January, Craig T.

PY - 1999

Y1 - 1999

N2 - Introduction: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go- related gene (HERG) 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.

AB - Introduction: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go- related gene (HERG) 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.

KW - Antihistamine

KW - Arrhythmia

KW - I(Kr)

KW - Long QT syndrome

KW - Potassium channels

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