Potent Inhibition of hERG Channels in a Mammalian Cell Line by the Anti-Diarrheal Agent Loperamide

Background: Loperamide is a peripherally-acting μ-opioid receptor agonist. It is available worldwide as an over-the-counter treatment for diarrhea. Like most opioids it is not currently known to be associated with prolongation of the QT interval or torsade de pointes. We recently described a case of torsade de pointes associated with high-dose loperamide consumption and therefore sought to determine in-vitro electrophysiological properties, given previously described proarrhythmic properties of methadone, a structurally similar synthetic opioid.

Methods: Effects of loperamide HCl on blockade of the human Ether-a-go-go (hERG) potassium channel ion current were assessed in Chinese hamster ovary (CHO-K1) cells stably expressing hERG to elucidate current amplitude and kinetics. The concentration of loperamide required to produce 50% inhibition (IC50) of hERG was assessed from the amplitude of tail currents following an activating pre-pulse. The ratio of IC50 to expected maximal serum concentration (Cmax) of supratherapeutic doses of loperamide (2 ng/ml) was calculated.

Results: The IC50 of hERG was approximately 40 nM for inhibition of tail currents (Figure). The IC50/Cmax ratio was 8.9 consistent with a concerning cardiac safety margin similar to methadone.

Conclusions: Loperamide is a highly potent hERG channel blocker, which suggests a causal association between loperamide and recent clinical cases of torsade de pointes. Given this finding, reconsideration of over-the counter availability of loperamide, by international regulatory agencies, seems warranted.