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Eur J Pharmacol. 2007 Jan 12;554(2-3):98-105. Epub 2006 Oct 18.

The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph.

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1
Institute of Biotechnology, University of Helsinki, Helsinki, Finland. hugh.chapman@orionpharma.com

Abstract

The human ether-à-go-go related gene (HERG) encodes the alpha-subunit of a delayed rectifier potassium channel important in the repolarisation of the cardiac action potential. Excessive action potential prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The acute effects of the novel prokinetic prucalopride were examined on heterologously expressed HERG channels in human embryonic kidney (HEK) 293 cells using the whole-cell patch-clamp technique. Prucalopride inhibited HERG channels in a concentration-dependent manner with an IC(50) of 4.1 microM. Prucalopride significantly slowed channel deactivation and recovery from inactivation, accelerated and altered the extent of inactivation. Similar concentration-dependency and kinetic changes were observed with the minor T897 polymorphic HERG variant. Prucalopride block was frequency-independent due to rapid state-dependent block, with binding occurring in the open and inactivated states. Though prucalopride blocks HERG channels this is unlikely to be significant at clinically relevant concentrations.

PMID:
17109852
DOI:
10.1016/j.ejphar.2006.10.019
[Indexed for MEDLINE]
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