Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2

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The aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2.


The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2.


Propafenone and mexiletine inhibited phenacetin O-deethylation with IC50 values of 29 and 37 μM, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC50 > 1 mM). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC50 values ranging from 86 to 704 μM. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2.


These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.

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