Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites

• Published in: Biochemical pharmacology 1995-09, Vol.50 (6), p.833-837
• Main Authors: Ching, Michael S., Blake, Carolyn L., Ghabrial, Hany, Ellis, S.Wynne, Lennard, Martin S., Tucker, Geoffrey T., Smallwood, Richard A.
• Format: Article
• Language: English
• Subjects: Anti-Arrhythmia Agents - pharmacology; Biological and medical sciences; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450 2D6; Dextromethorphan - metabolism; dihydroquinidine; General and cellular metabolism. Vitamins; Humans; Kinetics; Medical sciences; metabolic inhibition; Microsomes - enzymology; Microsomes, Liver - enzymology; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Pharmacology. Drug treatments; quinidine; Quinidine - analogs & derivatives; Quinidine - metabolism; Quinidine - pharmacology; quinidine metabolites; Recombinant Proteins - antagonists & inhibitors; Saccharomyces cerevisiae - enzymology; Substrate Specificity
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(95)00207-G

The inhibitory effects of dihydroquinidine, quinidine and several quinidine metabolites on cytochrome P450 2D6 (CYP2D6) activity were examined. CYP2D6 heterologously expressed in yeast cells O-demethylated dextromethorphan with a mean K m of 5.4 μM and a V max of 0.47 nmol/min/nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 metabolic activity (mean K i = 0.027 and 0.013 μM, respectively) in yeast microsomes and in human liver microsomes. The metabolites, 3-hydroxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibited CYP2D6, but their K i values (0.43 to 2.3 μM) were one to two orders of magnitude weaker than the values for quinidine and dihydroquinidine. There was a trend towards an inverse relationship between K i and lipophilicity ( r = −0.90, N = 5, P = 0.07), as determined by the retention-time parameter k′ using reverse-phase HPLC. Thus, although the metabolites of quinidine have the capacity to inhibit CYP2D6 activity, quinidine and the impurity dihydroquinidine are the important inhibitors of CYP2D6.