Mexiletine pharmacokinetics

Kusumoto M, Ueno K, Oda A, Takeda K, Mashimo K, Takaya K, Fujimura Y, Nishihori T, Tanaka K. Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men. Clin Pharmacol Ther 2001 69(3) 104-7. 

Vozeh S, Katz G, Steiner V, Eollath E. Population pharmacokinetic parameters in patients treated with oral mexiletine. Eur J Clin Pharmacol 1982 23 445-51. 

Maeda Y, Funakoshi S, Nakamura M, Fukuzawa M, Kugaya Y, Yamasaki M, Tsukiai S, Murakami T, Takano M. Possible mechanism for pharmacokinetic interaction between lidocaine and mexiletine. Clin Pharmacol Ther 2002 7I(5) 389-97. 

Mexiletine is a class Ib antidysrhythmic drug, similar in action to lidocaine, but it can be given orally. Its adverse effects occur in up to 50% of patients (1) and withdrawal is often necessary (2). The most common adverse effects are on the cardiovascular and central nervous systems. The pharmacokinetics, clinical use, and adverse effects and interactions of mexiletine have been reviewed widely (3-8). 

Grech-Belanger O. Clinical pharmacokinetics of mexiletine. Clin Progr Electrophysiol Pacing 1986 4 553. 

Lledo P, Abrams SM, Johnston A, Patel M, Pearson RM, Turner P. Influence of debrisoquine hydroxylation phenotype on the pharmacokinetics of mexiletine. Eur J Clin Pharmacol 1993 44(l) 63-7. 

Kusumoto M, Ueno K, Tanaka K, Takeda K, Mashimo K, Kameda T, Fujimura Y, Shibakawa M, Guzman WM, Laplante S. Lack of pharmacokinetic interaction between mexiletine and omeprazole. Ann Pharmacother 1998 32(2) 182-4. 

Labbe L, O Hara G, Lefebvre M, Lessard E, Gilbert M, Adedoyin A, Champagne J, Hamelin B, Turgeon J. Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings. Clin Pharmacol Ther 2000 68(l) 44-57. 

FIGURE 10.3 Effect of concomitantly administered mexiletine (Mx 200 mg Q8h) on the clearance of theophyUine (mean SD, p < 0.05) as determined by a retrospective analysis of theophylline pharmacokinetic data in 348 patients obtained from rontinely performed therapeutic drug monitoring. (Modified from Meibohm and Wegener. )... 

The fact that the metabolism of mexiletine cosegregates with debrisoquine hydroxylation was not known until recently [112]. Initial studies [129,130] on the stereoselective pharmacokinetics of mexiletine did not distinguish between poor and extensive metabolizers of debrisoquine in their study subjects (Table 13). These studies showed modest or no stereoselectivity in the systemic clearance, the renal clearance, and the terminal plasma half-life of the drug [129,130]. In 1993, Turgeon and colleagues [112] reported the kinetics of the individual enantiomers of mexiletine after a single dose of the racemate in 10 EMs and 4 PMs in the absence and presence of steady-state... 

Table 13 Stereoselective Pharmacokinetics (MeaniSD) of Oral Mexiletine After the Administration of the Racemate... 

In more recent studies, Turgeon and colleagues have reported the effects of coadministration of caffeine [131] or propafenone [132] on the stereoselective pharmacokinetics of mexiletine in poor and extensive metabolizers of debrisoquine. Caffeine, a substrate for CYP1A2, did not significantly change the plasma eoncentrations of mexiletine enantiomers in either PMs or EMs [131]. However, it resulted in a slight decrease ( 15%) in the urinary recovery of N-hydroxymexiletine generated from the R enantiomer in both EMs and PMs [131]. The metabolism of the S enantiomer was not affected because the N-hydroxymexiletine recovered in urine is mostly from the R enantiomer. 

In contrast to caffeine, propafenone coadministration significantly reduced the metabolism of both enantiomers of mexiletine in EMs [132]. However, it did not have a significant effect on the pharmacokinetics of mexiletine enantiomers in PMs. In fact, after coadministration of propafenone to EMs, the plasma concentration-time profiles and pharmacokinetics of mexiletine enantiomers in these subjects were not distinguishable from those in PMs [132]. These results are in agreement with the inhibitory effects of propafenone on the CYP2D6 pathway and are similar to those obtained with quinidine, another CYP2D6 inhibitor (Table 13). 

Kwok, D.W. Kerr, C.R. McErlane, K.M. Pharmacokinetics of mexiletine enantiomers in healthy human subjects. A study of the in vivo serum protein binding, salivary excretion and red blood cell distribution of the enantiomers. Xenobiotica 1995, 25, 1127-1142. 

Six healthy subjects were given a single 200-mg dose of mexiletine before and after faking fluconazole 200 mg daily for 7 days. Two of the subjects were given fluconazole 400 mg daily for a further 7 days. No significant changes in the pharmacokinetics of mexiletine were seen. The clinical outcome of concurrent use in patients was not studied, but there appear to be no adverse reports in the literature. No special precautions appear to be necessary if these drugs are used concurrently. 

The pharmacokinetics of mexiletine were not altered by cimeti-dine or ranitidine. Cimetidine can reduce the gasitric adverse effects of mexiletine. 

Omeprazole does not appear to affect the pharmacokinetics of mexiletine. 

A pharmacokinetic study showed that the mean plasma levels of mexiletine (400 mg orally followed by 200 mg 2 hours later) in the first 3 hours were more than 50% lower in 6 patients who had suffered a myocardial infarction and who had been given diamorphine 5 to 10 mg or morphine lOto 15 mg than in 4 patients who had not been given opioids. In addition, the AUCo.8 was 38.6% lower in those who had received opioids. ... 

The observation that 3 patients had unusually low plasma mexiletine levels while taking phenytoin prompted a pharmacokinetic study in 6 healthy subjects. After taking phenytoin 300 mg daily for a week, the mean AUC and half-life of a single 400-mg dose of mexiletine were reduced by an average of about 50% (half-life reduced from 17.2 to 8.4 hours). ... 

Serum theophylline levels are increased by mexiletine and toxicity may occur. Tocainide has only a small and probably clinically unimportant effect on theophylline pharmacokinetics. 

---