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- W2584745693 abstract "A significant percentage of drugs that are removed from the market are withdrawn due to unintentional drug-ion channel interactions in heart cells that result in an alteration of electrical wave propagation in the heart. Therefore, understanding and quantifying dose-response relationships between drugs and ion channels is a topic of significant importance for drug development. Drug effect on the inward rectifier K+ channel IKr is of particular interest due to its link to long QT syndrome and arrhythmias such as Torsades de Pointes. Currently, the dose-dependent change in single cell peak IKr current in response to a voltage-step protocol is often used to determine drug potency (IC50). This behavior can then be reproduced by modeling the drug effect as a dose dependent scaling of the current conductance (GKr). How well this simple model reproduces dose-response relationships between a drug and action potential (AP) or wave propagation properties, however, is not clear. Mathematical simulations can be used to investigate this question, and to develop better methods for measuring and modeling drug-ion channel interactions. We compared models of five synthetic drugs, each binding a different conformational state of a modified version of the Mazhari (2001) IKr Markov model. Each of the drugs generated similar peak current dose-response curves in voltage-step in silico experiments, but produced very different AP duration (APD) dose-response behavior when incorporated into the ten Tusscher (2004) and Hund-Rudy (2004) AP models. Scaling GKr in a dose-dependent fashion, to reproduce the peak current voltage-step response described above, did not accurately reproduce the APD dose-response of any of the five drugs. These findings suggest that novel experimental and modeling methods are needed to more accurately capture drug-ion channel interactions. Our simulations show that an AP clamp protocol more clearly differentiated the five drugs than standard voltage-step protocols. We then used simulations of the five synthetic drugs to investigate alternative modeling strategies to more accurately capture drug-ion channel and drug-AP dose-response relationships." @default.
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- W2584745693 date "2006-05-01" @default.
- W2584745693 modified "2023-10-16" @default.
- W2584745693 title "P5-25" @default.
- W2584745693 doi "https://doi.org/10.1016/j.hrthm.2006.02.803" @default.
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