Multi-Ion channel inhibition profiles: a quest for mechanistic understanding of safe drugs
Hai Huang 1, Michael Pugsley 2, Michael Accardi 1, Kim Bujold 1, Alexis Ascah 1, Samir Abtout 1, Mylène Pouliot 1 and Simon Authier 1,2
- Citoxlab North America, Laval, QC, Canada
- Purdue Pharma L.P., Cranbury, NJ, USA
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Background: hERG/IKr inhibition has been considered as a major risk factor for arrhythmia in drug development for nearly two decades with known limitations. A mechanistic understanding of ion channel interaction during the cardiac action potential has emerged as a strategy to identify proarrhythmic risk, beyond a simple measure of hERG/IKr inhibition. Currently, multiple ion channel inhibition screening is proposed to evaluate early and late repolarization effects. The purpose of this analysis was to evaluate a quantitative method to compare multi-ion channel inhibition profiles.
Methods: HEK 293 cells stably expressing ion channels were used in the manual whole-cell configuration. IC50 values for ion channels (Nav1.5, Kv4.3, Cav1.2, hERG, KvLQT1 and Kir2.1) were normalized for IKr inhibition and the resulting ratios were subjected to statistical comparison.
Results: Cisapride showed a dose-dependent inhibition on multiple channels with IC50 values (µM) of 0.0138 for hERG, 0.81 for Cav1.2, 20.2 for Nav1.5, 0.85 for KvLQT1, 15.4 for Kv4.3, and >10 for Kir 2.1. The IC50 values (µM) obtained from terfenadine were 0.018 (hERG), 0.71 (Cav1.2), 4.8 (Nav1.5), 4.70 (KvLQT1), 3.26 (Kv4.3) and >10 (Kir 2.1). For verapamil, IC50 values (µM) were 0.53 (hERG), 16.7 (Cav1.2), 11.9 (Nav1.5), 9.4 (KvLQT1), >10 (Kv4.3) and >100 (Kir2.1), respectively. After normalizing to hERG IC50, cisapride ratios were significantly different from verapamil ( p=0.034, t test). Ratios for terfenadine versus cisapride were not significantly different.
Conclusion: Multiple ion channel inhibition can help evaluate potential effects on the cardiac action potential, and estimate the proarrhythmic risk in patients. This analysis evaluated a simple quantitative strategy to compare multiple ion channel inhibition profiles.
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