Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment
Article first published online: 3 JUL 2012
Copyright © 2012 John Wiley & Sons, Ltd.
Journal of Applied Toxicology
Volume 32, Issue 10, pages 858–866, October 2012
How to Cite
Wiśniowska, B., Mendyk, A., Fijorek, K., Glinka, A. and Polak, S. (2012), Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment. J. Appl. Toxicol., 32: 858–866. doi: 10.1002/jat.2784
- Issue published online: 29 AUG 2012
- Article first published online: 3 JUL 2012
- Manuscript Revised: 14 MAY 2012
- Manuscript Accepted: 14 MAY 2012
- Manuscript Received: 30 MAR 2012
- L-type calcium channel;
- QT interval
Evaluation of the proarrhythmic potential of an investigated compound is now an integral element of the safety profile required for the approval of new drugs. The human ether-à-go-go-related gene (hERG) channel blocking potency is regarded as a surrogate marker of the proarrhythmic risk at the early stages of the research and development process. However, there is no straight correlation between QT prolongation and TdP occurrence probability, and hERG inhibition potential can be an inadequate predictor of QT prolongation. The L-type calcium channel plays a pivotal role in cardiomyocytes' physiology. Thus the main aim of this study was to develop a predictive model for drug-triggered CaL channel inhibition and also the assessment of drug–multichannel interaction effects on the heart rate-corrected QT interval. The data set, consisting of 123 records describing in vitro experimental settings, measured IC50 values and calculated physico-chemical properties for 72 various chemicals, was collected. The models were tested in a modified 10-fold cross-validation procedure. The generalization ability of the best model was as follows: root mean squared error (RMSE) = 1.10, normalized root mean squared error (NRMSE) = 16.09%. Out of the 10 most important variables, 5 described conditions of the in vitro experiments thus their description and experiment's conditions standardization might be the key to the models better performance. The simulations performed with the ToxComp system showed that the hERG block alone causes concentration-dependent QT prolongation, whereas when multichannel block is regarded, the effect could be reversed. For that reason, the multichannel interaction of tested compounds should be taken into consideration, in order to make the proarrhythmic risk assessment more reliable. Copyright © 2012 John Wiley & Sons, Ltd.