Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites.
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.
Ching
M S
MS
Department of Medicine, University of Melbourne, Heidelberg Repatriation Hospital, Victoria, Australia.
Blake
C L
CL
Ghabrial
H
H
Ellis
S W
SW
Lennard
M S
MS
Tucker
G T
GT
Smallwood
R A
RA
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
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