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.