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The hERG potassium channel and hERG screening for drug-induced torsades de pointes.
Pharmacol Ther. 2008 Aug; 119(2):118-32.P&T

Abstract

Drug-induced torsades de pointes (TdP) arrhythmia is a major safety concern in the process of drug design and development. The incidence of TdP tends to be low, so early pre-clinical screens rely on surrogate markers of TdP to highlight potential problems with new drugs. hERG (human ether-à-go-go-related gene, alternative nomenclature KCNH2) is responsible for channels mediating the 'rapid' delayed rectifier K+ current (IKr) which plays an important role in ventricular repolarization. Pharmacological inhibition of native IKr and of recombinant hERG channels is a shared feature of diverse drugs associated with TdP. In vitro hERG assays therefore form a key element of an integrated assessment of TdP liability, with patch-clamp electrophysiology offering a 'gold standard'. However, whilst clearly necessary, hERG assays cannot be assumed automatically to provide sufficient information, when considered in isolation, to differentiate 'safe' from 'dangerous' drugs. Other relevant factors include therapeutic plasma concentration, drug metabolism and active metabolites, severity of target condition and drug effects on other cardiac ion channels that may mitigate or exacerbate effects of hERG blockade. Increased understanding of the nature of drug-hERG channel interactions may ultimately help eliminate potential hERG blockade early in the design and development process. Currently, for promising drug candidates integration of data from hERG assays with information from other pre-clinical safety screens remains essential.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Cardiovascular Research Laboratories, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom. jules.hancox@bristol.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18616963

Citation

Hancox, Jules C., et al. "The hERG Potassium Channel and hERG Screening for Drug-induced Torsades De Pointes." Pharmacology & Therapeutics, vol. 119, no. 2, 2008, pp. 118-32.
Hancox JC, McPate MJ, El Harchi A, et al. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther. 2008;119(2):118-32.
Hancox, J. C., McPate, M. J., El Harchi, A., & Zhang, Y. H. (2008). The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacology & Therapeutics, 119(2), 118-32. https://doi.org/10.1016/j.pharmthera.2008.05.009
Hancox JC, et al. The hERG Potassium Channel and hERG Screening for Drug-induced Torsades De Pointes. Pharmacol Ther. 2008;119(2):118-32. PubMed PMID: 18616963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The hERG potassium channel and hERG screening for drug-induced torsades de pointes. AU - Hancox,Jules C, AU - McPate,Mark J, AU - El Harchi,Aziza, AU - Zhang,Yi Hong, Y1 - 2008/06/18/ PY - 2008/05/27/received PY - 2008/05/27/accepted PY - 2008/7/12/pubmed PY - 2009/1/14/medline PY - 2008/7/12/entrez SP - 118 EP - 32 JF - Pharmacology & therapeutics JO - Pharmacol. Ther. VL - 119 IS - 2 N2 - Drug-induced torsades de pointes (TdP) arrhythmia is a major safety concern in the process of drug design and development. The incidence of TdP tends to be low, so early pre-clinical screens rely on surrogate markers of TdP to highlight potential problems with new drugs. hERG (human ether-à-go-go-related gene, alternative nomenclature KCNH2) is responsible for channels mediating the 'rapid' delayed rectifier K+ current (IKr) which plays an important role in ventricular repolarization. Pharmacological inhibition of native IKr and of recombinant hERG channels is a shared feature of diverse drugs associated with TdP. In vitro hERG assays therefore form a key element of an integrated assessment of TdP liability, with patch-clamp electrophysiology offering a 'gold standard'. However, whilst clearly necessary, hERG assays cannot be assumed automatically to provide sufficient information, when considered in isolation, to differentiate 'safe' from 'dangerous' drugs. Other relevant factors include therapeutic plasma concentration, drug metabolism and active metabolites, severity of target condition and drug effects on other cardiac ion channels that may mitigate or exacerbate effects of hERG blockade. Increased understanding of the nature of drug-hERG channel interactions may ultimately help eliminate potential hERG blockade early in the design and development process. Currently, for promising drug candidates integration of data from hERG assays with information from other pre-clinical safety screens remains essential. SN - 0163-7258 UR - https://www.unboundmedicine.com/medline/citation/18616963/The_hERG_potassium_channel_and_hERG_screening_for_drug_induced_torsades_de_pointes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0163-7258(08)00105-8 DB - PRIME DP - Unbound Medicine ER -