Systems pharmacology for cardiac ion channels

Abstract

Systems pharmacology brings the approaches of systems biology to the field of pharmacology. It seeks to understand drug actions and side effects in the context of the biological complex systems. Simulation studies in systems pharmacology are becoming an increasingly essential tool for proper in vitro-in vivo extrapolation so that we can understand in vivo consequences upon administration of drugs to humans. In addition, it may make a suggestion about new targets and strategies for therapeutics of complex diseases. Principle of systems pharmacology therefore seems to make major contributions to drug discovery and development. During recent years, there have been attempts to formulate the effects of drug on ion channels and to understand the actions and side effects in vivo. This review discusses how studies in systems pharmacology provided a deeper understanding of the safety and efficacy of existing medications and would be going to contribute to the drug development in the future. We cover the issues of hERG channel-targeting drugs and arrhythmias. Recently we have demonstrated that some of Class III antiarrhythmic agents have dual effect on hERG channel; these drugs not only block hERG current as generally defined but also facilitate the voltage-dependent activation so that it can increase hERG currents at low potentials close to the threshold for channel activation. Moreover, we also found that some of non-cardiac agents such as haloperidol and fluoxetine have facilitation effect on hERG channel. Therefore the clinical importance of hERG facilitation needs further characterization. We then discuss how the facilitation of hERG channel contributes IKr current and cardiac action potential. We propose that this mechanism prevents the excessive prolongation of APD and development of early afterdepolarization (EAD), one of the substrates for torsade de pointes induced by drugs, suggesting that the facilitation effect suppresses the proarrhythmia risk. Taken together, these types of analyses can lead to new therapeutic options while improving rational drug development and the safety assessment.