Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings.

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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 Jul;68(1):44-57. doi: 10.1067/mcp.2000.108023.

PubMed ID

10945315 [ View in PubMed

]

Abstract

BACKGROUND AND OBJECTIVE: Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. METHODS: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). RESULTS: In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(-)-mexiletine (from 41+/-11 L/h to 28+/-7 L/h) and S-(+)-mexiletine (from 43+/-15 L/h to 29+/-11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. CONCLUSION: Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Mexiletine	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details
Propafenone	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate Inhibitor	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Propafenone Tipranavir	The serum concentration of Propafenone can be increased when it is combined with Tipranavir.