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

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Wei X, Dai R, Zhai S, Thummel KE, Friedman FK, Vestal RE

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

J Pharmacol Exp Ther. 1999 May;289(2):853-8.

PubMed ID
10215663 [ View in PubMed
]
Abstract

Mexiletine, lidocaine, and tocainide are class IB antiarrhythmic drugs that are used for the treatment of ventricular arrhythmias and are known to inhibit 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 isozyme. The inhibitory effect of mexiletine, lidocaine, and tocainide on cytochrome CYP1A2 in human liver microsomes was examined with methoxyresorufin O-demethylase activity as an index of the catalytic activity of this P-450 isozyme. The kinetic inhibition types and Ki values were determined by Lineweaver-Burk plots and Dixon plots, respectively. Molecular modeling was used to assess the interaction of these agents with the CYP1A2 active site. Methoxyresorufin O-demethylase activity was inhibited 67 +/- 8%, 20 +/- 5%, and 7 +/- 4% by 2 mM mexiletine, lidocaine, and tocainide, respectively. Mexiletine and lidocaine exhibited competitive inhibition with Ki 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 charge interaction between mexiletine and the Asp313 side chain in the CYP1A2 active site was found, and varying degrees of hydrogen bond formation between these three compounds and the CYP1A2 active site were observed. The in vitro inhibitory potencies in human liver microsomes (mexiletine > lidocaine > tocainide) are consistent with the structural interactions found in a molecular model of the active site of CYP1A2.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
LidocaineCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Inhibitor
Details
MexiletineCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
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interactions in your software
Aminophylline
Mexiletine		The metabolism of Aminophylline can be decreased when combined with Mexiletine.
Bromotheophylline
Mexiletine		The metabolism of Bromotheophylline can be decreased when combined with Mexiletine.
Caffeine
Mexiletine		The metabolism of Caffeine can be decreased when combined with Mexiletine.
Dyphylline
Mexiletine		The metabolism of Dyphylline can be decreased when combined with Mexiletine.
Lomifylline
Mexiletine		The metabolism of Lomifylline can be decreased when combined with Mexiletine.