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 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.
Wei
X
X
Clinical Pharmacology and Gerontology Research Unit, Department of Veterans Affairs Medical Center, Mountain States Medical Research Institute, Boise, Idaho, USA.
Dai
R
R
Zhai
S
S
Thummel
K E
KE
Friedman
F K
FK
Vestal
R E
RE
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology*; D008801:Mexiletine / Q000494:pharmacology*; D008958:Models, Molecular; D010088:Oxidoreductases / Q000378:metabolism; D016677:Tocainide / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D008801:Mexiletine; D016677:Tocainide; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase