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Most drugs have effects attributed to actions at sites other than those that are intended. In many cases these off-target effects have adverse consequences, though in some instances these effects may be neutral or even beneficial. Many off-target effects involve either direct or indirect actions on ion channels. Hence, electrophysiological approaches can be employed to screen drugs for effects on ion channels and thereby predict their off-target actions. The pharmaceutical industry routinely uses cellular expression systems and cloned channels to quickly screen thousands of compounds to eliminate those that have well known adverse ion channel effects, such as inhibition of the Kv11.1 potassium channel encoded by the human Ether-a-go-go related gene (hERG). However, these methods are not well-suited to predicting many other off-target effects mediated by actions on ion channels natively expressed in specific tissues. We have employed a more directed electrophysiological approach to evaluate a small number of compounds (e.g. drugs with known or predicted adverse effects) to identify ion channel targets that might explain their actions. This chapter will describe this approach in some detail and illustrate its use with some specific examples.

Use of Patch Clamp Electrophysiology to Identify Off-Target Effects of Clinically Used Drugs