title: Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites.
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.
authors.affiliation: Department of Medicine, University of Melbourne, Heidelberg Repatriation Hospital, Victoria, Australia.
authors.forename: M S
authors.initials: MS
authors.lastname: Ching
authors.forename: C L
authors.initials: CL
authors.lastname: Blake
authors.forename: H
authors.initials: H
authors.lastname: Ghabrial
authors.forename: S W
authors.initials: SW
authors.lastname: Ellis
authors.forename: M S
authors.initials: MS
authors.lastname: Lennard
authors.forename: G T
authors.initials: GT
authors.lastname: Tucker
authors.forename: R A
authors.initials: RA
authors.lastname: Smallwood
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011802:Quinidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013379:Substrate Specificity
chemical_list: D000889:Anti-Arrhythmia Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D011994:Recombinant Proteins; D003915:Dextromethorphan; C014486:hydroquinidine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine