The role of lipophilicity in the inhibition of polymorphic cytochrome P450IID6 oxidation by beta-blocking agents in vitro

Life Sci. 1991;48(23):2259-65. doi: 10.1016/0024-3205(91)90341-8.


The importance of lipophilicity as a determinant of the affinity of beta-adrenoceptor blocking agents for a specific human hepatic monooxygenase--cytochrome P450IID6 (responsible for the debrisoquine-type of oxidation polymorphism)--was investigated in vitro by estimating the inhibition constants of a series of compounds in a microsomal system with monitoring of the kinetics of dextromethorphan O-demethylation. Lipophilicity is a key predictor of the affinity of beta-blocking drugs for cytochrome P450IID6 and of their potential to cause specific competitive drug interactions, but more complex structural factors appear to be important as well. A high lipophilicity is also a necessary, but not a sufficient condition for these compounds to be metabolized by cytochrome P450IID6.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Dextromethorphan / metabolism
  • Dextrorphan / metabolism
  • Humans
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Microsomes, Liver / enzymology
  • Oxidation-Reduction
  • Oxidoreductases, O-Demethylating / antagonists & inhibitors*
  • Oxidoreductases, O-Demethylating / metabolism
  • Solubility


  • Adrenergic beta-Antagonists
  • Cytochrome P-450 Enzyme Inhibitors
  • Isoenzymes
  • Dextrorphan
  • Dextromethorphan
  • Cytochrome P-450 Enzyme System
  • Oxidoreductases, O-Demethylating
  • dextromethorphan O-demethylase