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Enzymes in addition to CYP3A4 and 3A5 mediate N ‐demethylation of dextromethorphan in human liver microsomes
Author(s) -
Wang Yi,
Unadkat Jashvant D.
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199910)20:7<341::aid-bdd195>3.0.co;2-f
Subject(s) - dextrorphan , dextromethorphan , cyp3a4 , microsome , cyp2b6 , indinavir , chemistry , cyp3a , cytochrome p450 , pharmacology , cyp2c8 , enzyme , biochemistry , biology , immunology , virus , sida , viral disease
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 μ m 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. Copyright © 1999 John Wiley & Sons, Ltd.