title: Enzymes in addition to CYP3A4 and 3A5 mediate N-demethylation of dextromethorphan in human liver microsomes.
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.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000996:Antitussive Agents / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D003915:Dextromethorphan / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D003917:Dextrorphan / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D000996:Antitussive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D003917:Dextrorphan; C028657:3-methoxymorphinan; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human