Clinical Pharmacokinetics of Mexiletine
- 1 January 1999
- journal article
- review article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 37 (5), 361-384
- https://doi.org/10.2165/00003088-199937050-00002
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 600mg. 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.Keywords
This publication has 100 references indexed in Scilit:
- Single-dose quinidine treatment inhibits mexiletine oxidation in extensive metabolizers of debrisoquineLife Sciences, 1991
- Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart diseaseInternational Journal of Cardiology, 1991
- Influence of Mexiletine on the Pharmacokinetics of Theophylline in Healthy VolunteersThe Journal of Clinical Pharmacology, 1991
- Mexiletin bei terminaler Niereninsuffizienz und verschiedenen DialyseverfahrenKlinische Wochenschrift, 1989
- Pharmacokinetics of Mexiletine in the ElderlyThe Journal of Clinical Pharmacology, 1989
- Effect of oral combination therapy with mexiletine and quinidine on left and right ventricular functionAmerican Heart Journal, 1988
- Oral mexiletine-theophylline interactionInternational Journal of Cardiology, 1987
- Efficacy of combination therapy with mexiletine and a type IA agent for inducible ventricular tachyarrhythmias secondary to coronary artery diseaseThe American Journal of Cardiology, 1985
- Effects of oral mexiletine on left and right ventricular functionThe American Journal of Cardiology, 1984
- MexiletineDrugs, 1979