Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m‐hydroxymexiletine

Abstract

Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m-hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time- and voltage-dependent manner, with an IC50 of 3.7 ± 0.7 μmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m-hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 μmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta-position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds.

Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment

“…Similar results have been previously shown for flecainide (Harris et al, 2013). We observed comparable trends for quinidine and mexiletine both of which have been demonstrated to block hERG and voltage-gated sodium channels (Gualdani et al, 2015). In addition to the Phase-I compounds evaluated as part of the CiPA initiative we sought to assess the effect of additional well known hERG channel inhibitors such as cisapride and dofetilide side by side with E4031, flecainide and quinidine in a dose-dependent manner (Fig.…”

“…3D and Table 3). 5) Mexiletine -Mexiletine is a class-Ib anti-arrhythmic compound which is known to block the action of the late sodium channel Nav1.5 and hERG channel (Gualdani et al, 2015). Application of mexiletine to hiPSC-CMs showed significant inhibition of the FP amplitude (88 ± 5% at 30 μM concentration compared to baseline) and prolonged FPD at 10 μM ( Fig.…”

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

“…Hence, to mitigate the pro‐arrhythmic effect of hERG blockade, the IC 50 values for the L‐type calcium and/or the late I Na currents should be fairly close to the one for I Kr . Examples are ranolazine (Antzelevitch et al, ; Crumb et al, ), verapamil (Obejero‐Paz et al, ; Crumb et al, ) and mexiletine (Gao et al, ; Antzelevitch et al, ; Gualdani et al, ; Crumb et al, ). There are no well‐documented reports of TdP in association with their use.…”

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

“…The preparation of 1a was performed under both traditional (method A) and microwaves conditions (method B) [31].…”