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Title: Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites.
Austin Authors: Ching, M S;Blake, C L;Ghabrial, Hany;Ellis, S W;Lennard, M S;Tucker, G T;Smallwood, R A
Affiliation: Department of Medicine, University of Melbourne, Heidelberg Repatriation Hospital, Victoria, Australia
Issue Date: 7-Sep-1995
Publication information: Biochemical Pharmacology; 50(6): 833-7
Abstract: 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 Km of 5.4 microM and a Vmax of 0.47 nmol/min/nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 metabolic activity (mean Ki = 0.027 and 0.013 microM, respectively) in yeast microsomes and in human liver microsomes. The metabolites, 3-hydroxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibited CYP2D6, but their Ki values (0.43 to 2.3 microM) were one to two orders of magnitude weaker than the values for quinidine and dihydroquinidine. There was a trend towards an inverse relationship between Ki 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.
Gov't Doc #: 7575645
Type: Journal Article
Subjects: Anti-Arrhythmia Agents.pharmacology
Cytochrome P-450 CYP2D6
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System.metabolism
Microsomes, Liver.enzymology
Mixed Function Oxygenases.antagonists & inhibitors.metabolism
Quinidine.analogs & derivatives.metabolism.pharmacology
Recombinant Proteins.antagonists & inhibitors
Saccharomyces cerevisiae.enzymology
Substrate Specificity
Appears in Collections:Journal articles

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