AimsThe 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. Methods 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. Results Propafenone and mexiletine inhibited phenacetin O-deethylation with IC 50 values of 29 and 37 mm, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC 50 >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 IC 50 values ranging from 86 to 704 mm. 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. Conclusions 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.Keywords: CYP1A2, phenacetin O-deethylation, human liver microsomes, mexiletine, propafenone I antiarrhythmic drug, has been reported to elevate plasma Introduction levels of concomitantly administered theophylline [19][20][21][22][23][24], by inhibiting 1-and 3-demethylation and 8-hydroxylation Cytochrome P450 1A2 (CYP1A2), an isoform of the CYP1A subfamily [1], accounts for about 10 to 15% of the total CYP of theophylline [19,20]. Recent studies using human liver microsomes and cDNA-expressed human CYP isoforms content of human livers [2]. This enzyme is known to catalyse the metabolism of imipramine [3], propranolol [4], indicated that CYP1A2 is the enzyme mainly responsible for the 1-and 3-demethylation and 8-hydroxylation of clozapine [5], caffeine [6], theophylline [7] and phenacetin [6,8]. The kinetic disposition of these drugs is altered by the theophylline in humans [25, 26]. Several studies using rat liver microsomes also showed that mexiletine inhibits administration or exposure to inducers or inhibitors of CYP1A2. For example, the clearance of propranolol [9], ethoxyresorufin O-dealkylation catalysed by CYP1A1, another isoform of the CYP1A subfamily [27]. However, in clozapine [10] and theophylline [11] is greater in smokers than in nonsmokers, as a result of marked induction of vivo [28,29] and in vitro [30,31] studies showed that mexiletine is mainly metabolized by CYP2D6. Therefore, CYP1A2 by cigarette smoking. On the other hand, the plasma concentrations of imipramine [12], clozapine [13], it remains obscure as to whether the pharmacokinetic interaction between theophylline and mexiletine occurs by caffeine [14,...
