Chemical formula: C₁₁H₁₇NO Molecular mass: 179.259 g/mol PubChem compound: 4178
Mexiletine blocks sodium channels with a stronger potency in situations of excessive burst of action potentials (use-dependent block) and/or prolonged depolarization (voltage-dependent block), as occurring in diseased tissues, rather than on physiological excitability (resting or tonic block). Mexiletine is, therefore, mostly active on muscle fibres subject to repeated discharges (such as skeletal muscles). It improves myotonic symptoms by decreasing muscle stiffness through reduction of the delay of muscle relaxation.
Mexiletine is rapidly and almost completely absorbed following oral administration with a bioavailability of about 90% in healthy subjects. Peak plasma concentrations following oral administration occur within 2 to 3 hours. No notable accumulation of mexiletine was observed after repeated administration.
Food does not affect the rate or extent of absorption of mexiletine. Therefore, mexiletine can be taken with or without food.
Mexiletine is rapidly distributed in the body; its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals.
Mexiletine is weakly bound to plasma proteins (55%). Mexiletine crosses the placental barrier and diffuses into breast milk.
Mexiletine is mainly (90%) metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. The metabolic degradation proceeds via various pathways, including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxymexiletine.
The influence of CYP2D6 phenotype on mexiletine metabolism has been extensively investigated. Mexiletine pharmacokinetics are characterised by significantly lower total and renal clearance resulting in prolonged elimination half-life, higher exposure, and lower volume of distribution in poor metabolisers compared to extensive metabolisers.
Approximately 10% is excreted unchanged by the kidney.
Mexiletine is eliminated slowly in humans (with a mean elimination half-life of 10 hours, ranging from 5 to 15 hours).
Excretion of mexiletine essentially occurs through the kidney (90% of the dose, including 10% as unchanged mexiletine).
Mexiletine excretion may increase when the urinary pH is acidic, compared to normal or alkaline pH. In a clinical study, 51% of the mexiletine dose was excreted via the kidney at a urinary pH of 5, compared to 10% at normal pH. Changes in urinary pH are not expected to affect efficacy or safety.
A linear relationship between mexiletine dose and plasma concentration has been observed in the dose range of 83 to 500 mg.
CYP2D6 polymorphism affects mexiletine pharmacokinetics. Individuals who are CYP2D6 poor metabolisers (PM) exhibit higher mexiletine concentrations than CYP2D6 intermediate (IM), extensive (i.e. normal) or ultra-rapid (UM) metabolisers. The proportions of different ethnic populations across these various classes are tabulated below.
| Ethnicity | Poor metabolisers (PM) | Intermediate metabolisers (IM) | Ultra-rapid metabolisers(UM) |
|---|---|---|---|
| Caucasians | Up to 10% | 1-2% | Up to 10% |
| Africans | Up to 10% | - | Up to 5% |
| Asians | Up to 5% | More than 50% | Up to 2% |
In population pharmacokinetic analyses, weight was found to influence mexiletine pharmacokinetics.
There is no clinically relevant effect of age on the exposure of mexiletine in adults.
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development. The main observed effects in rats and/or dogs were vomiting, diarrhoea, tremor, ataxia, convulsions and tachycardia. However, these studies were not performed in accordance with contemporary standards and are, hence, of unclear clinical relevance.
The studies in rats on carcinogenic potential were negative, but not performed in accordance with current standards and therefore of unclear clinical relevance. The negative genotoxicity potential does not indicate an increased carcinogenic risk of treatment with mexiletine.
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