INHIBITION BY FLUOXETINE OF CYTOCHROME-P450 2D6 ACTIVITY

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver micro somes by fluoxetine and its major metabolite norfluoxetine was confirm ed (apparent inhibition constant values, 0.2 mumol/L). Several other s erotonergic agents were also found to be competitive inhibitors of thi s genetically polymorphic enzyme. The O-demethylation ratio of dextrom ethorphan that expressed CYP2D6 activity in 19 patients receiving fluo xetine fell in the region of the antimode separating the O-demethylati on ratio values observed in 208 extensive metabolizers from 15 poor me tabolizers of a control group of healthy subjects. Inhibition of CYP2D 6 activity in patients undergoing treatment with fluoxetine or other s erotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzym e. Other in vitro studies indicated that CYP2D6 catalyzes the O-demeth ylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both exte nsive and poor metabolizer individuals, indicating that these compound s are not selective inhibitors of CYP2D6 activity.