Evaluation of the Pharmacological Activity of the Major Mexiletine Metabolites on Skeletal Muscle Sodium Currents

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2006 Aug 22

PMID 16921388

Citations 9

Authors

M De Bellis

A De Luca

F Rana

M M Cavalluzzi

A Catalano

G Lentini

C Franchini

V Tortorella

D Conte Camerino

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites.

Experimental Approach: To determine their contribution to the clinical activity of Mex, p-hydroxy-mexiletine (PHM), hydroxy-methyl-mexiletine (HMM), N-hydroxy-mexiletine (NHM) (phase I reaction products) and N-carbonyloxy beta-D-glucuronide (NMG) (phase II reaction product) were tested on sodium currents (I(Na)) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP=-140, -100, -70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline-gap voltage-clamp method.

Key Results: All the hydroxylated derivatives blocked the sodium channel in a voltage- and use-dependent manner. The PHM, HMM and NHM metabolites were up to 10-fold less effective than the parent compound. However, HMM showed a greater use-dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound.

Conclusions And Implications: Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.

Citing Articles

Blockers of Skeletal Muscle Na1.4 Channels: From Therapy of Myotonic Syndrome to Molecular Determinants of Pharmacological Action and Back.

De Bellis M, Boccanegra B, Cerchiara A, Imbrici P, De Luca A Int J Mol Sci. 2023; 24(1).

PMID: 36614292 PMC: 9821513. DOI: 10.3390/ijms24010857.

Benzothiazole-Containing Analogues of Triclocarban with Potent Antibacterial Activity.

Catalano A, Rosato A, Salvagno L, Iacopetta D, Ceramella J, Fracchiolla G Antibiotics (Basel). 2021; 10(7).

PMID: 34356724 PMC: 8300675. DOI: 10.3390/antibiotics10070803.

The Different Facets of Triclocarban: A Review.

Iacopetta D, Catalano A, Ceramella J, Saturnino C, Salvagno L, Ielo I Molecules. 2021; 26(9).

PMID: 34068616 PMC: 8126057. DOI: 10.3390/molecules26092811.

Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential.

De Bellis M, Sanarica F, Carocci A, Lentini G, Pierno S, Rolland J Front Pharmacol. 2018; 8:907.

PMID: 29379434 PMC: 5770958. DOI: 10.3389/fphar.2017.00907.

Sodium channel slow inactivation as a therapeutic target for myotonia congenita.

Novak K, Norman J, Mitchell J, Pinter M, Rich M Ann Neurol. 2014; 77(2):320-32.

PMID: 25515836 PMC: 4315705. DOI: 10.1002/ana.24331.

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