Predictive analysis of the fate of pharmaceuticals in the environment

Les substances pharmaceutiques sont classées comme contaminants environnementaux émergents et suscitent une attention croissante du fait de leurs effets potentiellement néfastes sur les écosystèmes. Après excrétion ou élimination inappropriée, les médicaments vont se retrouver dans les eaux de surface, souterraines voire de consommation. De nombreuses études écotoxicologiques ont pour objet la mesure de leurs impacts sur les écosystèmes. Pour autant, ces études portent essentiellement sur le médicament lui-même alors que nombre d'entre eux sont susceptibles de se transformer dans l'environnement selon des processus biotiques (microorganismes) et/ou abiotiques (traitements chimiques, photodégradation). Les produits de transformations (PTs) ainsi formés vont d'une part, progressivement remplacer le médicament parent dans l'environnement, et d'autre part y exprimer une écotoxicité potentielle. Face à ce problème, nous nous proposons à partir d'un médicament largement utilisé, de procéder à la synthèse de ses PTs plausibles et à la mise au point de méthode de détection dans des matrices complexes. L'accès aux PTs suivra une approche pluridisciplinaire faisant appel à la bioconversion, l'électro-Fenton et l'oxydation électrochimique. L'analyse comparative des composés obtenus par ces différentes approches permettra de sélectionner les PTs les plus probablesPharmaceuticals as well as personal care products are classified as emerging pollutants of increasing concern due to possible negative impacts on ecosystems. They are constantly introduced in sewage treatment plants either through excretion, or disposal by flushing of unused or expired medication, or directly within the sewage effluents of plants or hospitals. They end up in surface and ground waters and can even be found in drinking water. Many studies report on adverse effects on terrestrial and aquatic organisms. Pharmaceuticals have complex chemical structures capable of reacting in an aqueous medium under the action of chemical, biological or physical agents. Thus, the transformation products (TPs) gradually replace the parent drug in the environment. In addition these transformation products constitute markers of past or current presence of the drug in the environment. Faced with this problem, we believe it is necessary to synthesize the transformation products of the parent compounds to development their detection. The proposed method consists, firstly, to prepare the largest number of (TPs) of a particular drug using three complementary approaches : bioconversion, electro-Fenton and electrochemical oxidation. A second step is to identify the structures which are the most likely present in the environment. Expected advances are the development of a predictive methodology applicable to the study of any molecule involved in environmental ris

Predictive analysis of the fate of pharmaceuticals in the environment

Les substances pharmaceutiques sont classées comme contaminants environnementaux émergents et suscitent une attention croissante du fait de leurs effets potentiellement néfastes sur les écosystèmes. Après excrétion ou élimination inappropriée, les médicaments vont se retrouver dans les eaux de surface, souterraines voire de consommation. De nombreuses études écotoxicologiques ont pour objet la mesure de leurs impacts sur les écosystèmes. Pour autant, ces études portent essentiellement sur le médicament lui-même alors que nombre d'entre eux sont susceptibles de se transformer dans l'environnement selon des processus biotiques (microorganismes) et/ou abiotiques (traitements chimiques, photodégradation). Les produits de transformations (PTs) ainsi formés vont d'une part, progressivement remplacer le médicament parent dans l'environnement, et d'autre part y exprimer une écotoxicité potentielle. Face à ce problème, nous nous proposons à partir d'un médicament largement utilisé, de procéder à la synthèse de ses PTs plausibles et à la mise au point de méthode de détection dans des matrices complexes. L'accès aux PTs suivra une approche pluridisciplinaire faisant appel à la bioconversion, l'électro-Fenton et l'oxydation électrochimique. L'analyse comparative des composés obtenus par ces différentes approches permettra de sélectionner les PTs les plus probablesPharmaceuticals as well as personal care products are classified as emerging pollutants of increasing concern due to possible negative impacts on ecosystems. They are constantly introduced in sewage treatment plants either through excretion, or disposal by flushing of unused or expired medication, or directly within the sewage effluents of plants or hospitals. They end up in surface and ground waters and can even be found in drinking water. Many studies report on adverse effects on terrestrial and aquatic organisms. Pharmaceuticals have complex chemical structures capable of reacting in an aqueous medium under the action of chemical, biological or physical agents. Thus, the transformation products (TPs) gradually replace the parent drug in the environment. In addition these transformation products constitute markers of past or current presence of the drug in the environment. Faced with this problem, we believe it is necessary to synthesize the transformation products of the parent compounds to development their detection. The proposed method consists, firstly, to prepare the largest number of (TPs) of a particular drug using three complementary approaches : bioconversion, electro-Fenton and electrochemical oxidation. A second step is to identify the structures which are the most likely present in the environment. Expected advances are the development of a predictive methodology applicable to the study of any molecule involved in environmental ris

Preparative access to transformation products (TPs) of furosemide: a versatile application of anodic oxidation

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Anticipating the fate and impact of organic environmental contaminants: a new approach applied to the pharmaceutical furosemide.

International audienceThe presence of trace levels of organic contaminants in the environment is currently an environmental concern. When these contaminants are subjected to environmental transformations, environmental transformation products (ETPs) are obtained, whose structures often remain unknown. The absence of information concerning these new compounds makes them unavailable and consequently makes their environmental detection as well as their (eco)toxicological study impossible. This report describes a multidisciplinary approach that seeks to both anticipate the fate and evaluate the impact of organic environmental contaminants. Our approach consists of three steps. First, isolated and fully characterized transformation products (TPs) of the parent molecule are obtained. In the second step, the parent molecule is subjected to environmentally relevant transformations to identify plausible ETPs. The detection of previously characterized TPs allows the concomitant identification of plausible ETPs. The third step is devoted to the toxicological evaluation of the identified plausible ETPs. Such an approach has recently been applied to furosemide and has allowed the identification of its main TPs. This report now seeks to identify and evaluate toxicologically plausible ETPs of this drug, which is also known as an environmental contaminant

A new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration

International audiencePharmaceuticals and their by-products are increasingly a matter of concern, because of their unknown impacts on human health and ecosystems. The lack of information on these transformation products, which toxicity may exceed that of their parent molecules, makes their detection and toxicological evaluation impossible.Recently we characterized the Pyridinium of furosemide (PoF), a new transformation product of furosemide, the most widely used diuretic and an emerging pollutant. Here, we reveal PoF toxicity in SH-SY5Y cells leading to alpha-synuclein accumulation, reactive oxygen species generation, and apoptosis. We also showed that its mechanism of action is mediated through specific inhibition of striatal respiratory chain complex I, both in vitro by direct exposure of striatum mitochondria to PoF, and in vivo, in striatal mitochondria isolated from mice exposed to PoF for 7 days in drinking water and sacrificed 30 days later. Moreover, in mice, PoF induced neurodegenerative diseases hallmarks like phospho-Serine129 alpha-synuclein, tyrosine hydroxylase decrease in striatum, Tau accumulation in hippocampus. Finally, we uncovered PoF as a new metabolite of furosemide present in urine of patients treated with this drug by LC/MS. As a physiopathologically relevant neurodegeneration inducer, this new metabolite warrants further studies in the framework of public health and environment protection

Electro-oxidation of the pharmaceutical Furosemide: Kinetics, mechanism and by-products

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