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Inhibition by fluoxetine of cytochrome P450 2D6 activity
Author(s) -
Otton S Victoria,
Wu Dafang,
Joffe Russell T,
Cheung Siu Wah,
Sellers Edward M
Publication year - 1993
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1993.43
Subject(s) - cyp2d6 , dextromethorphan , fluoxetine , pharmacology , microsome , chemistry , demethylation , cytochrome p450 , metabolite , non competitive inhibition , active metabolite , enzyme , serotonin , biochemistry , medicine , gene expression , receptor , dna methylation , gene
Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 μmol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O ‐demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O ‐demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O ‐demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity. Clinical Pharmacology and Therapeutics (1993) 53, 401–409; doi: 10.1038/clpt.1993.43