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

Biochem Pharmacol. 1995 Sep 7;50(6):833-7. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Arrhythmia Agents / pharmacology*
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dextromethorphan / metabolism*
  • Humans
  • Kinetics
  • Microsomes / enzymology
  • Microsomes, Liver / enzymology
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism*
  • Quinidine / analogs & derivatives*
  • Quinidine / metabolism
  • Quinidine / pharmacology
  • Recombinant Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae / enzymology*
  • Substrate Specificity


  • Anti-Arrhythmia Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Recombinant Proteins
  • Dextromethorphan
  • hydroquinidine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2D6
  • Quinidine