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 methoxyresorufinO-demethylase activity as an index of the catalytic activity of this P-450 isozyme. The kinetic inhibition types andK i 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 K ivalues 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.
Footnotes
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Send reprint requests to: Robert E. Vestal, M.D., Covance Clinical and Periapproval Services Inc., 2121 N. California Blvd., Suite 500, Walnut Creek, CA 94596. E-mail: bob.vestal{at}covance.com
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↵1 This work was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), the National Institutes of Health (National Cancer Institute), and the Mountain States Medical Research Institute.
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↵2 Present address: Office of Pharmaceutical Sciences, U.S. Food and Drug Administration, HFD-870,13B-17, Parklawn Building, 5600 Fishers Lane, Rockville, MD 20857.
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↵3 Present address: Clinical Pharmacokinetics Unit, Cellular and Clinical Pharmacology Section, National Cancer Institute, National Institutes of Health, Building 10, Room 5A-01, 9000 Rockville Pike, Bethesda, MD 20892.
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↵4 Present address: Covance Clinical and Periapproval Services Inc., 2121 N. California Blvd., Suite 500, Walnut Creek, CA 94596.
- Abbreviations:
- CYP1A2
- cytochrome P-450 1A2
- MROD
- methoxyresorufin O-demethylase
- Received July 16, 1998.
- Accepted December 3, 1998.
- U.S. Government
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