Enzymes in addition to CYP3A4 and 3A5 mediate N-demethylation of dextromethorphan in human liver microsomes

Biopharm Drug Dispos. 1999 Oct;20(7):341-6. doi: 10.1002/(sici)1099-081x(199910)20:7<341::aid-bdd195>3.0.co;2-f.

Abstract

Both indinavir and troleandomycin (CYP3A inhibitors) are incapable of completely inhibiting dextromethorphan metabolism to 3-methoxymorphinan in human liver microsomes. It is hypothesized that CYPs in addition to CYP3A4 and 3A5 contribute to this biotransformation. The effect of CYP-selective inhibitors on the residual 3-methoxymorphinan activity in human liver microsomes (i.e. in the presence of 30 microM indinavir, a selective CYP3A4 and 3A5 inhibitor) was measured to identify these enzymes. At this concentration, indinavir completely inhibited the formation of 3-methoxymorphinan by rCYP3A4 and rCYP3A5. In addition, the formation kinetics of 3-methoxymorphinan in rCYPs was measured. Only CYP2B6, 2C8 and 2C18 were considered likely candidates as contributors to residual 3-methoxymorphinan activity. The residual 3-methoxymorphinan activity was highly correlated with CYP2B6 activity as measured by CYP2B6 antibody (r(2)=0.90, p<0.001) and by orphenadrine (r(2)=0.97, p<0.001), but was not correlated (r(2)=0.12, p>0.05) with CYP2C8 activity. Collectively, these findings suggest that CYP2B6 is a major contributor towards residual 3-methoxymorphinan activity, while CYP2C8 and 2C18 are either minor contributors or do not contribute to this metabolic process.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Blocking / pharmacology
  • Antitussive Agents / metabolism*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dealkylation
  • Dextromethorphan / analogs & derivatives
  • Dextromethorphan / chemistry
  • Dextromethorphan / metabolism*
  • Dextrorphan / chemistry
  • Dextrorphan / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / metabolism*

Substances

  • Antibodies, Blocking
  • Antitussive Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Dextrorphan
  • 3-methoxymorphinan
  • Dextromethorphan
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human