Effects of combined treatment with cognitive enhancer memantine and antidepressant fluoxetine on CYP2D2 metabolic activity in rats.
2011
The drug-drug interactions can result in alterations of the
therapeutical responses. The present study was designed to
investigate possible pharmacokinetic interactions between the
cognitive agent memantine and the antidepressant fluoxetine
combined often in treatments of cognitive disorders including
Alzheimer disease. The attention was focused on changes of the
cytochrome P450 2D2 isoenzyme activity in two animal models.
METHODS AND DESIGN: The tested drugs were administered alone or
in a combination to rat males and their effects on the 2D2
isoenzyme activity was determined after in vivo administration.
The levels of marker dextromethorphan, its 2D2 specific
metabolite dextrorphan were analyzed in plasma of rats and
using the model of isolated perfused rat liver in the perfusion
medium. The dextromethorphan/ dextrorphan (DEM/DEX) metabolic
ratios were determined as a sign of inhibitory influences on
CYP2D2. RESULTS: The analyses showed elevation of DEM/DEX
metabolic ratio after all treatments: a) memantine, b)
fluoxetine and c) memantine+fluoxetine, however the results
were not completely identical. The intensity of inhibitory
effects on the CYP2D2 activity were: memantine < memantine +
fluoxetine < fluoxetine. CONCLUSION: The results presented
suggest that the clinical pharmacotherapeutical approach to
combine memantine with fluoxetine is from the point of view of
pharmacokinetic drug-drug interaction on the level of CYP2D2
isoenzyme safe and even of benefit as memantine could elicit a
suppression of the inhibitory influence of fluoxetine.
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