Broly, F.

Caron, J.

Lacroix, D.

Lhermitte, M.

Libersa, C.

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Interaction of propafenone and mexiletine 

JACC Vet. 22, No. 7 
Decemlxr 1993:2058-62 
2 
ventricular cavity muscte mass during the 1st year after an in 
myocardial infarction occur in a nonparallel fashion. The observa- 
tions, in fact, are vindicated by prior ex 
El, DPHUL 
Deparrmpnl of Cardiology 
Georgelow Univer&y 
Washittgron, D.C. 20007 
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shape and orthogonal wall stress adaptations during the first year after anterior wall 
myocardial infarction [abstract]. I Am Coil Cardiol 1993;21 Slsppl A:403A. 
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We congratulate Yeung-kai-Wab and colleagues (1) fc~r their in&z- 
esting report concerning combination drug therapy usiaag pro- 
pafenone (a class IC antiarrhythmic agent) and mexiletine (a class I
agent) in patients with a history of sustained ventricular tachycardia 
that had not responded to propafenone or proca~~am~de alone or in 
combination. 
Undoubkdly, the electrophysidogic properties of these antiar- 
rhythmic drugs are partially due to specific interactions with sodium 
channels, as described in the modulated receptor model proposed by 
Hondeghem and Katzung (2). We disagree, however, that “little is 
known about pharmacokinetic interaction between propafenone and 
mexiletine” (I). The metabolism of propafenone (as well as that of 
encainide and flecainide) is genetically mediated, following the same 
oxidation pathway as that of debrisoqnine and sparteine through the 
P450 2 II6 cytochrome (also known as P45Q dbl or CYFED6). It 
follows then that, like debrisoquine, these drugs exhibit genetic 
polymorphism in patients who are either “extensive” or “poor” 
metabolizers (3-6). It has also been demonstrated (7-9) that mexi- 
letine metabolism, both in vitro and in vivo, is probably linked to the 
debrisoquinekparteiae pathway, with similar genetic polymor- 
phism. 
Therefore a combination of the two tested drugs could have a 
synergistic effect not only because of specific electrophysiologic 
properties, but also because of an alteration of the metabolism of 
one or both d.i”rigs, which could tead TV a dramatic increase irt the 
plasma levels of the parent drug and a decrease in the levels of its 
metabolites. The absence of blood level determinations in this study 
makes it impossible for the authors to make any statement concem- 
ing such drug interactions. 
fects, and study of a correiation between blood levels and clinical 
as tn take these consi 
Furthermore, because m&iple studies have ed that mex- 
iletine only significantly prolongs the cycle len the ~~~~ced 
ventricular tachycardia , i? scsolb e argued that the improvement in
antiarrhyth cacy of the tested drugs used in c~mb~~at~on 
ight amainly be linked to an increase in the plas levels of 
propafenone as a consequence of mexiletine compe n for the 
same metabolic pathway. 
As a result of these pharmacokinetic alterations, one might 
observe an increase in eit er !RE e!ectrophysiologic 
side effects of the dmg, or both, with aH the attendant conse- 
quences. 
To avoid unexpected and untoward consequences, the choice of 
a~t~a~byt~mic combinations and the choice of dosage should be 
made with great care, especially when the dnngs in question have a 
common metabolic pathway. 
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nation for the treatment of sustained ventricular tacbycardia. J Am Cell Cardiol 
1992;20: 547-5 t. 
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on eocainide pharmacokinetics and phannacodynamics: nfluence of genetic polymor- 
phism. J Pharmacoi Exp Ther 198%249:134-42. 
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influence of the sparteineldebrisoquioe phenotype on the disposition ofRecainide. Clin 
Pharmacd Ther 1989;45:562-7. 
6. Haefeli WE, Bargetzi MI, Follath F. Meyer UA. Patent inhibition of cytochrome 
P45wlliD6 [debrisoquin Chydroxylase) by flecainide invitro and in vivo. J Cardiovasc 
Pharmacol 1990;15:776-9. 
7. Broly F. Libersa C. Lhermitte M. Mexiletine metabolism in vitro by human liver. Drug 
Metab Dispos 1990:18:!62-9. 
8. Broly F. Libersa C. Lhermitte M. Dupuis B. Inhibitory studies of mexiletioe and 
dextrometborphan oxider in human liver microsomes. Biochem Pharmacol 199&39: 
1045-53. 
9. Broly F. VanDamme N. Libersa C. Lnermjtte 1111. Tire metabolism of mexiletine in
relation to tbe debrisoquineisparteine-type polymorphism of drug oxidation. Br J Clin 
Phsrmawl 1981;3?:459-66. 
We thank Libersa and colleagues for their thoughtful comments. 
The additional information regarding the metabolism of mexiletine 
may be very important o the understanding of the propafenone- 
mexiletine interaction. The potential competition for metabolism 


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Interaction of propafenone and mexiletine

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