Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents.
OBJECTIVE
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.


METHODS
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.


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
Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.
De Bellis
M
M
Unit of Pharmacology, Department of Pharmacobiology, University of Bari, Bari, Italy.
De Luca
A
A
Rana
F
F
Cavalluzzi
M M
MM
Catalano
A
A
Lentini
G
G
Franchini
C
C
Tortorella
V
V
Conte Camerino
D
D
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008801:Mexiletine / Q000378:metabolism* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D011893:Rana esculenta; D026941:Sodium Channel Blockers / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D008801:Mexiletine