Inhibition of human liver cytochrome P-450 1A2 by the class IB antiarrhythmics mexiletine, lidocaine, and tocainide

Mexiletine, lidocaine, and tocainide are class IB antiarrhythmic drugs that are used for the treatment of ventricular arrhythmias and are known to inh ibit drug metabolism. The objectives of this study were to characterize the inhibitory effects of mexiletine, lidocaine, and tocainide on cytochrome P -450 1A2 (CYP1A2) activity in human liver microsomes and to evaluate their relative inhibitory potencies by using a molecular model of this P-450 isoz yme. The inhibitory effect of mexiletine, lidocaine, and tocainide on cytoc hrome CYP1A2 in human liver microsomes was examined with methoxyresorufin O -demethytase activity as an index of the catalytic activity of this P-450 i sozyme. The kinetic inhibition types and K-i values were determined by Line weaver-Burk plots and Dixon plots, respectively. Molecular modeling was use d to assess the interaction of these agents with the CYP1A2 active site. Me thoxyresorufin O-demethylase activity was inhibited 67 +/- 8%, 20 +/- 5%, a nd 7 +/- 4% by 2 mM mexiletine, lidocaine, and tocainide, respectively. Mex iletine and lidocaine exhibited competitive inhibition with K-i values of 0 .28 +/- 0.12 mM and 1.54 +/- 0.74 mM, respectively, whereas the inhibition type of tocainide could not be determined because of its weak potency. A ch arge interaction between mexiletine and the Asp313 side chain in the CYP1A2 active site was found, and varying degrees of hydrogen bond formation betw een these three compounds and the CYP1A2 active site were observed. The in vitro inhibitory potencies in human liver microsomes (mexiletine > lidocain e > tocainide) are consistent with the structural interactions found in a m olecular model of the active site of CYP1A2.