Clinical Pharmacokinetics of Mexiletine

Abstract

Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely absorbed following oral administration with a bioavailability of about 90%. Peak plasma concentrations following oral administration occur within 1 to 4 hours and a linear relationship between dose and plasma concentration is observed in the dose range of 100 to 600 mg. Mexiletine is weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 hours). It undergoes stereoselective disposition caused by extensive metabolism. Eleven metabolites of mexiletine are presently known, but none of these metabolites possesses any pharmacological activity. The major metabolites are hydroxymethyl-mexiletine, p-hydroxy-mexiletine, m-hydroxy-mexiletine and N-hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy-mexiletine and m-hydroxy-mexiletine is genetically determined and cosegregates with polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6] activity. On the other hand, CYP1A2 seems to be implicated in the N-oxidation of mexiletine. Various physiological, pathological, pharmacological and environmental factors influence the disposition of mexiletine. Myocardial infarction, opioid analgesics, atropine and antacids slow the rate of absorption, whereas metoclopramide enhances it. Rifampicin (rifampin), phenytoin and cigarette smoking significantly enhance the rate of elimination of mexiletine, whereas ciprofloxacin, propafenone and liver cirrhosis decrease it. Cimetidine, ranitidine, fluconazole and omeprazole do not modify the disposition of mexiletine. Conversely, mexiletine is known to alter the disposition of other drugs, such as caffeine and theophylline. Factors affecting the elimination of mexiletine may be clinically important and dosage adjustments are often necessary.

Effects of Mexiletine on Electrical Field Stimulation-Induced Contractile Responses in the Ipsilateral and Contralateral Vasa Deferentia after Unilateral Testicular Torsion/Detorsion

“…In the mexiletine group, after being dissolved in the water, 50 mg/kg mexiletine (Sigma, St. Louis, Mo., USA) were administered intraperitoneally at the first hour of the torsion [16][17][18] .…”

“…Each vas deferens obtained from the ipsi-and contralateral site was dissected into 2-cm strips including both the epididymal and prostatic portions, and was mounted in 10-ml organ baths with a resting tension of 1.0 g containing a physiological salt solution (Krebs-Henseleit solution) of the following composition (in m M ): NaCl 118.0, KCl 4.7, CaCl 2 2.5, NaHCO 3 25.0, MgSO 4 1.2, KH 2 PO 4 1.2, glucose 11.0 [18] . The pH of the solution was 7.4 after being bubbled with a gas mixture of 95% O 2 -5% CO 2 ; the solution was maintained at 37 ° C.…”

Genetic and Epigenetic Factors Affecting Cytochrome P450 Phenotype and Their Clinical Relevance

“…It is metabolized to various metabolites by CYP2D6 and other enzymes. Due to CYP2D6, a minor gene-concentration effect seems to be present, but because of other elimination pathways it is not predictable for the dose (Labbe & Turgeon, 1999).…”

CYP2D6-Mediated Mexiletine-Protein Adduct Formation

“…In humans, mexiletine undergoes extensive metabolism in the liver to several pharmacologically inactive metabolites. 6) A CYP enzyme CYP2D6 has predominant roles in oxidation of aromatic rings and aromatic methyl groups. 7) On the other hands, N-hydroxylation was recently shown to be mediated mainly by CYP1A2.…”