RELATIVE POTENCY OF MEXILETINE, LIDOCAINE, AND TOCAINIDE AS INHIBITORS OF RAT-LIVER CYP1A1 ACTIVITY

Mexiletine and tocainide are lidocaine congeners that share similar ch emical structures. Clinical studies suggest that the in vivo inhibitor y effect of mexiletine on the CYP1A family of isoforms is substantiall y greater than that of tocainide, We investigated the inhibitory prope rty of mexiletine, lidocaine, and tocainide on the in vitro activity o f the cytochrome P4501A1 (CYP1A1) isozyme in the rat, Hepatic microsom es were prepared from rat livers induced with 3-methylcholanthrene. Th e rate of ethoxyresorufin-O-dealkylation (EROD) was used as an index o f CYP1A1 activity, V-max and K-M of the reactions were determined from Lineweaver-Burk plots. The K-i values for the inhibitors were derived from Dixon plots. Results showed that mexiletine is a competitive inh ibitor, lidocaine is mixed inhibitor, and tocainide is a noncompetitiv e inhibitor of EROD. The K-i values for mexiletine and tocainide were 0.30 +/- 0.02 mM and 12.4 +/- 0.7 mM, respectively, Two K-i 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 differ ence in potency, which is most likely attributable to the change in th e chemical composition in the aliphatic chain among the compounds, sug gests that these compounds may be useful probes for studying the mecha nism of the interaction with the active site of CYP1A1.