Effects of 4‐Aminopyridine on Cloned hERG Channels Expressed in Mammalian Cells

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Abstract
Introduction.  Non‐clinical evaluation of a medication's potential to induce cardiac toxicity is recommended by regulatory agencies. 4‐Aminopyridine (fampridine) is a potassium channel blocker with the demonstrated ability to improve walking ability in patients with multiple sclerosis. We evaluated the in vitro effects of 4‐aminopyridine on the human ether‐à‐go‐go‐related gene (hERG) channel current, since hERG current inhibition is associated with QT interval prolongation—a precursor to torsade de pointes (TdP).Methods.  4‐Aminopyridine was evaluated in concentrations ranging from 0.1 mM to 30 mM in human embryonic kidney 293 cells stably transfected with the hERG gene; terfenadine 60 nM was used as a positive control.Results and Discussion.  We observed concentration‐dependent inhibition of hERG current with 4‐aminopyridine doses between 0.3 and 30 mM. The concentration of 3.8 mM resulting in 50% inhibition (IC50) is approximately three orders of magnitude higher than expected therapeutic plasma concentrations, suggesting 4‐aminopyridine has low potential for prolonging QT interval or inducing TdP.

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