Clinical pharmacokinetics of mexiletine

Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely abso rbed following oral administration with a bioavailability of about 90%, Pea k plasma concentrations following oral administration occur within 1 to 4 h ours and a linear relationship between dose and plasma concentration is obs erved in the dose range of 100 to 600mg. Mexiletine is weakly bound to plas ma 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 me tabolism. Eleven metabolites of mexiletine are presently known, but none of these metabolites possesses any pharmacological activity. The major metabo lites are hydroxymethyl-mexiletine, p-hydroxy-mexiletine-hydroxy-mexiletine and N-hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy -mexiletine and m-hydroxy-mexiletine is genetically determined and cosegreg ates with polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6 ] activity. On the other hand, CYP1A2. seems to be implicated in the N-oxid ation of mexileline. Various physiological, pathological, pharmacological and environmental fact ors influence the disposition of mexiletine. Myocardial infarction, opioid analgesics, atropine and antacids slow the rate of absorption, whereas meto clopramide enhances it. Rifampicin (rifampin), phenytoin and cigarette smok ing significantly enhance the rate of elimination of mexiletine, whereas ci profloxacin, propafenone and liver cirrhosis decrease it. Cimetidine, ranit idine, fluconazole and omeprazole do not modify the disposition of mexileti ne. Conversely, mexiletine is known to alter the disposition of other drugs , such as caffeine and theophylline. Factors affecting the elimination of m exiletine may be clinically important and dosage adjustments are often nece ssary.