POTENT INHIBITION OF YEAST-EXPRESSED CYP2D6 BY DIHYDROQUINIDINE, QUINIDINE, AND ITS METABOLITES

The inhibitory effects of dihydroquinidine, quinidine and several quin idine metabolites on cytochrome P450 2D6 (CYP2D6) activity were examin ed. CYP2D6 heterologously expressed in yeast cells O-demethylated dext romethorphan with a mean K-m of 5.4 mu M and a V-max of 0.47 nmol/min/ nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 me tabolic activity (mean K-i = 0.027 and 0.013 mu M, respec tively) in y east microsomes and in human liver microsomes. The metabolites, 3-hydr oxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibite d CYP2D6, but their K-i values (0.43 to 2.3 mu M) were one to two orde rs of magnitude weaker than the values for quinidine and dihydroquinid ine. 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 rete ntion-time parameter k' using reverse-phase HPLC. Thus, although the m etabolites of quinidine have the capacity to inhibit CYP2D6 activity, quinidine and the impurity dihydroquinidine are the important inhibito rs of CYP2D6.