Physiological modes of action of Fluoxetine and its human metabolites in algae

Are widely used pharmaceuticals and their transformation products of environmental concern and is biological activity retained in non-target organisms and after metabolism? These questions triggered the investigation of the ecotoxicity of the antidepressant fluoxetine and its human metabolites. Highest concentrations were up to 300 ng/L for fluoxetine and norfluoxetine. After oral uptake up to 75% of the daily dose are excreted via urine, thereof more than 10% unchanged fluoxetine as well as its pharmacologically active metabolite norfluoxetine, up to 20% hippuric acid and traces of p-trifluoromethylphenol. To assess the toxicity of these metabolites, the toxicity of the single compounds as well as of a mixture of fluoxetine and its metabolites were investigated. With two different algae tests the time dependence and sensitivity of effect endpoints related to efficiency of photosynthesis and growth, including reproduction, cell division and cell volume growth, yields information on the physiological mode of action. The effect pattern and a quantitative structure activity relationship (QSAR) analysis revealed that fluoxetine and norfluoxetine are specifically acting in algae, but the effect pattern was most similar to baseline toxicants. In mixture experiments, the non-specific endpoints showed concentration addition, whereas the more specific endpoints, like the inhibition of photosynthesis, typically showed less effect than predicted by concentration addition or independent action. Consequently the specific mode of action is of low intrinsic potency and influenced by baseline toxicity. In contrast, p-trifluoromethylphenol and hippuric acid are baseline toxicants