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Drugs and trafficking of ion channels: a new pro‐arrhythmic threat on the horizon?
Author(s) -
Heyden M A G,
Smits M E,
Vos M A
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707618
Subject(s) - herg , torsades de pointes , repolarization , ion channel , long qt syndrome , pharmacology , potassium channel , medicine , cardiac action potential , qt interval , electrophysiology , receptor
Tuning of functional expression levels of the ion channels that make up the cardiac action potential (AP) is crucial for preserving correct AP duration (APD) and QTc times. Many compounds inhibit human ether‐à‐go‐go related gene (hERG)‐mediated delayed rectifier currents and thus prolong cardiac repolarization that may cause life‐threatening arrhythmias like Torsades de Pointes. An increasing number of drugs are found to inhibit hERG function by a dual mechanism of short‐term channel block and long‐term trafficking defects that operate over different time and concentration scales. In safety screens at present used by pharmaceutical companies, the short‐term effect of channel block is covered. In contrast, specific screening for long‐term trafficking defects is not common, with the consequent risk of drugs that disturb trafficking entering the market. Whether that poses another pro‐arrhythmic threat for the patients treated has to be determined, but is not unlikely. British Journal of Pharmacology (2008) 153 , 406–409; doi: 10.1038/sj.bjp.0707618 ; published online 3 December 2007