INHIBITORY EFFECTS OF ANTIARRHYTHMIC DRUGS ON PHENACETIN O-DEETHYLATION CATALYZED BY HUMAN CYP1A2

Aims The aim of the study was to clarify whether the pharmacokinetic i nteraction between theophylline and mexiletine is mediated by inhibiti on or CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2. Methods The in hibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacet in O-deethylation, a marker reaction of CYP1A2, were studied using hum an Liver microsomes and cDNA-expressed CYP1A2. Results Propafenone and mexiletine inhibited phenacetin O-deethylation with IC50 values of 29 and 37 mu M, respectively. Disopyramide, procainamide and pilsicainid e produced negligible inhibition of phenacetin O-deethylation (IC50 > 1 mM). Amiodarone, bepridil, aprindine, lignocaine, flecainide and qui nidine inhibited phenacetin O-deethylation in a concentration-dependen t manner, although the inhibitory effects were relatively weak with IC 50 values ranging from 86 to 704 mu M. Propafenone and mexiletine sele ctively abolished the high-affinity component of phenacetin O-deethyla tion in human liver microsomes. In addition, propafenone and mexiletin e inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1 A2. Conclusions These data suggest that, among the antiarrhythmic drug s studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabol ized by CYP1A2.