Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings

Background and objective: Mexiletine and propafenone are often used concomi tantly and are metabolized by the same cytochrome P450 isozymes, namely CYP 2D6, CYP1A2, and probably CYP3A4, Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine an d propafenone. Methods: Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor me tabolizers of CYP2Db, received oral doses of mexiletine 100 mg two times da ily from day 1 to day 8 and oral doses of propafenone 150 mg two times dail y from day 5 to day 12, Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafe none alone (day 12). Results: In subjects in the extensive metabolizer group, coadministration o f 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 hydroxymethyl mexiletine, p-hydroxymexiletine, and m-hydroxpmexiletine in extensive metab olizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did no t alter the kinetics of mexiletine enantiomers in subjects in the poor meta bolizer group except for a slight decrease in the formation of hydroxymethy lmexiletine. Pharmacokinetic parameters of propafenone were not changed dur ing combined administration of mexiletine in subjects of either phenotype, Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR int ervals) were not modified during the combined administration of the drugs. Conclusion: Propafenone is a potent CYP2D6 inhibitor that may cause an incr ease in plasma concentrations of coadministered CYP2D6 substrates.