Relative potency of mexiletine, lidocaine, and tocainide as inhibitors of rat liver CYP1A1 activity.

Mexiletine and tocainide are lidocaine congeners that share similar chemical structures. Clinical studies suggest that the in vivo inhibitory effect of mexiletine on the CYP1A family of isoforms is substantially greater than that of tocainide. We investigated the inhibitory property of mexiletine, lidocaine, and tocainide on the in vitro activity of the cytochrome P4501A1 (CYP1A1) isozyme in the rat. Hepatic microsomes were prepared from rat livers induced with 3-methylcholanthrene. The rate of ethoxyresorufin-O-dealkylation (EROD) was used as an index of CYP1A1 activity. Vmax and KM of the reactions were determined from Lineweaver-Burk plots. The Ki values for the inhibitors were derived from Dixon plots. Results showed that mexiletine is a competitive inhibitor, lidocaine is a mixed inhibitor, and tocainide is a noncompetitive inhibitor of EROD. The Ki values for mexiletine and tocainide were 0.30 +/- 0.02 mM and 12.4 +/- 0.7 mM, respectively. Two Ki values for lidocaine were determined. They were 0.65 +/- 0.07 mM and 4.1 +/- 1.3 mM, respectively. The relative inhibitory potency of these agents on rat CYP1A1 activity is mexiletine > lidocaine > tocainide. This difference in potency, which is most likely attributable to the change in the chemical composition in the aliphatic chain among the compounds, suggests that these compounds may be useful probes for studying the mechanism of the interaction with the active site of CYP1A1.