Mexiletine

Synthesis and Toxicopharmacological Evaluation of m-Hydroxymexiletine, the First Metabolite of Mexiletine More Potent Than the Parent Compound on Voltage-Gated Sodium Channels

“…Indeed, mexiletine is metabolized in the liver by oxidation, deamination, reduction, and conjugation. , Unchanged mexiletine in urine accounts for only 10% of the administered dose . Eleven metabolites of mexiletine, most of which are eliminated as glucuronide conjugates, were identified, but none of them were found to possess any pharmacological activity. ,, Indeed, we recently demonstrated that two metabolites, hydroxymethylmexiletine (HMM, Figure ) and p -hydroxymexiletine (PHM), conserve only residual blocking activity on sodium currents recorded in skeletal muscle fibers, when compared to mexiletine. − In this paper we report the synthesis and biological activity of a minor metabolite of mexiletine, m -hydroxymexiletine (MHM), which in humans accounts for approximately 2% of an administered oral dose of mexiletine. Since mexiletine is clinically used as a racemic mixture, MHM and the parent compound were studied in this form.…”

Bioorthogonal Removal of 3-Isocyanopropyl Groups Enables the Controlled Release of Fluorophores and Drugs in Vivo

“…To corroborate that ICPr chemistry is compatible with living systems, we analyzed the phenomenological effects of releasing an active drug inside zebrafish (Figure a). We synthesized an ICPrc-prodrug of mexiletine (ICPrc-mex, Figure a), a voltage-gated sodium channel blocker, which induces cardiac arrhythmia and decreases heart rate . Incubation in ICPrc-mex containing medium (c = 0, 1, 10 μM) caused a dose-dependent decrease in heart rate in fish with implanted Tz-PS similar to the effect observed for the free drug, whereas no changes were observed in control fish bearing unmodified beads (Figure c).…”