A comprehensive method for the analysis of 11 target pharmaceuticals representing multiple therapeutic classes was developed for biological tissues (fish) and water. Water samples were extracted using solid phase extraction (SPE), while fish tissue homogenates were extracted using accelerated solvent extraction (ASE) followed by mixed-mode cation exchange SPE cleanup and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Among the 11 target pharmaceuticals analyzed, trimethoprim, caffeine, sulfamethoxazole, diphenhydramine, diltiazem, carbamazepine, erythromycin and fluoxetine were consistently detected in reclaimed water. On the other hand, caffeine, diphenhydramine and carbamazepine were consistently detected in fish and surface water samples. In order to understand the uptake and depuration of pharmaceuticals as well as bioconcentration factors (BCFs) under the worst-case conditions, mosquito fish were exposed to reclaimed water under static-renewal for 7 days, followed by a 14-day depuration phase in clean water. Characterization of the exposure media revealed the presence of 26 pharmaceuticals while 5 pharmaceuticals including caffeine, diphenhydramine, diltiazem, carbamazepine, and ibuprofen were present in the organisms as early as 5 h from the start of the exposure. Liquid chromatography ultra-high resolution Orbitrap mass spectrometry was explored as a tool to identify and quantify phase II pharmaceutical metabolites in reclaimed water. The resulting data confirmed the presence of acetyl-sulfamethoxazole and sulfamethoxazole glucuronide in reclaimed water. To my knowledge, this is the first known report of sulfamethoxazole glucuronide surviving intact through wastewater treatment plants and occurring in environmental water samples. Finally, five bioaccumulative pharmaceuticals including caffeine, carbamazepine, diltiazem, diphenhydramine and ibuprofen detected in reclaimed water were investigated regarding the acute and chronic risks to aquatic organisms. The results indicated a low potential risk of carbamazepine even under the worst case exposure scenario. Given the dilution factors that affect environmental releases, the risk of exposure to carbamazepine will be even more reduced.

Bioassays for baseline toxicity, which measure toxicants’ non-specific effects, have been shown in previous studies to effectively correlate with the increased presence of pharmaceuticals, personal care products, endocrine-disrupting compounds, and other synthetic organics in treated sewage effluent. This study investigated how the baseline toxicity of anthropogenic compounds-spiked wastewater changed during the treatment of biofiltration and ozone oxidation, as measured by the bioluminescence inhibition of the Vibrio fischeri bacterium. The water quality parameters of dissolved organic carbon, seven common anions, and fluorescence spectroscopy were used to corroborate and collate with the toxicity results. Water quality was evaluated on two bench-scale soil filtration columns, which were configured for pre-ozonation and post-ozonation. Both systems’ soil aerobically removed similar amounts of dissolved organic carbon, and the reduction ranged between 57.7% and 62.1% for the post-ozonation and pre-ozonation systems, respectively. Biological removal of DOC, protein-like, humic-like, and soluble microbial product-like material was highest in the first 28.5 cm of each 114 cm-long system. While bioluminescence inhibition showed that ozonation was effective at lowering baseline toxicity, this study’s bioassay procedure was a very poor indicator of soil filtration treatment; both system’s effluents were significantly more toxic than their non-ozonated influents.

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Le travail de thèse présenté dans ce manuscrit porte sur la caractérisation de l’exposition des organismes aquatiques à un produit pharmaceutique (PP) et sur l’étude des perturbations métaboliques associées. Un PP récemment inclus dans la liste de vigilance de la directive cadre sur l’eau européenne (2015/495/EC), le DCF, et un organisme du milieu marin, Mytilus galloprovincialis, ont été choisis comme modèles de travail. L’approche méthodologique développée est une combinaison de l’analyse ciblée et non-ciblée des métabolites endogènes et exogènes (l’endo- et le xéno-métabolome) présents chez l’organisme d’étude suite à une exposition au DCF. L’évaluation des effets du DCF chez la moule par approche ciblée a été conduite sur la base de son mode d’action connu chez l’Homme : la modulation de la synthèse des prostaglandines (PG). Les PGs sont impliquées dans diverses fonctions, telles que la reproduction et l’osmorégulation chez les organismes aquatiques, et d’autres voies métaboliques sont susceptibles d’être impactées. Les résultats obtenus ont permis de mettre en évidence une sous-modulation de la synthèse de la PGE2 chez les moules exposées au DCF. Par ailleurs, peu d’informations sont disponibles concernant la métabolisation du DCF chez les invertébrés. Pour étudier la biotransformation et les effets du DCF chez la moule, l’application d’une approche non-ciblée nous semblait prometteuse. L’étude du xéno-métabolome m’a permis de mettre en évidence la formation de 13 métabolites, dont 3 de phase I et 10 de phase II. Parmi ces métabolites, 5 sont référencés pour la première fois dans la littérature. Par la suite, l’étude de l’endo-métabolome a permis de révéler la modulation de deux voies métaboliques : le métabolisme de la tyrosine et le métabolisme du tryptophane. Les catécholamines et la sérotonine ressortent comme particulièrement impactées dans ces deux voies métaboliques. Chez la moule, ces métabolites sont impliqués dans des fonctions biologiques importantes : l’osmorégulation et la reproduction et sont en accord avec les études menées chez d’autres organismes aquatiques. Le travail effectué a permis de mettre en évidence que l’application de l’approche métabolomique à des questions environnementales est pertinente et performante pour étudier la biotransformation et les effets non-documentés (différent du mécanisme d’action connu) d’un produit pharmaceutique chez des organismes non-cibles, sans hypothèse a priori. / This PhD thesis describes an investigation of the metabolomic approach performances to characterize the pharmaceuticals environmental exposure and effects in non target organisms. The studied pharmaceutical was diclofenac (DCF), a non-steroidal anti-inflammatory drug recently included in the first watch list of the European Water Framework Directive (2015/495/EC), and the model organism was the Mediterranean mussel Mytilus galloprovincialis. The methodological approach combines target and non-targeted analysis of endogenous and exogenous metabolites in mussel, the endo- and the xeno-metabolome. DCF effects in mussel were investigated considering its known mode of action in human: the prostaglandins (PG) synthesis modulation. In aquatic organisms, PGs are involved in various biological functions, such as reproduction or osmoregulation. This targeted analysis allowed us to determine a PGE2 synthesis disruption with DCF exposure. Otherwise, little information is available about DCF biotransformation in invertebrates. To study DCF biotransformation in mussel, the application of a non-targeted approach seemed promising. This study allows the reveal 13 DCF metabolites formation of which 3 were phase I metabolites and 10 were phase II metabolites. Among them, 5 were described for the first time. Subsequently, the mussel’s endo-metabolome study showed the modulation of two pathways: the tyrosine and the tryptophan metabolism. Inside these pathways, the catecholamines and serotonin appeared as particularly impacted. In mussels, these compounds are involved in important biological functions: the osmoregulation and the reproduction. Such DCF effects are in accordance with those reported in other study conducted on aquatic organisms. The work conducted highlighted the relevance and pertinence of the metabolomic approach as a tool for environmental studies without a priori hypothesis, such as studying the biotransformation and unexpected effects of pharmaceuticals in non-target organisms.

Present methods for diagnosis of neurodegenerative diseases are rather limited and in clinical practise are missing. This thesis is focused on utilization of the positron emission tomography using isotope 64 Cu(II). For the project, two contrast agents were proposed containing ligand for Cu (II) coordination and thioflavine T derivative as fluorescent dye, also as a targeting compound. Structure of the thioflavine T derivative was defined by X-ray structural analysis. The selected fluorescent dye has a high affinity for incipient amyloids and, when bound to their structure, has enhanced fluorescent properties. The proposed ligands are tetraazacyclic. The first one is a diamide, where the thioflavin T derivative is part of a macrocyclic ring. The second selected ligand is linked to the thioflavin T derivative via a linker. Key words: complexes; pharmaceuticals; transition metals

Pharmaceuticals are micropollutants, that enter the environment mainly through Wastewater Treatment Plants (WWTPs). In this work microbial community has been studied in sediments of a stream, which is located near a WWTP. This sediment is contaminated with pharmaceuticals. The subject of this thesis was to determine the presence of pharmaceuticals and microbial community in this study site and to point out possible relationships between these factors. Twelve pharmaceuticals were identified at concentrations reaching levels of ng/g. The concentrations of the compounds form a gradient that decreases with the distance from WWTP. Microbial biomass was estimated using the analysis of phospholipid fatty acids and microbial community was described using next-generation DNA sequencing. The analysis of phospholipid fatty acids pointed out, that with the increasing distance from WWTP the amount of microbial biomass decreases. DNA sequencing revealed large microbial diversity in the studied sediment. For evaluation of the relationship between the microbial community and pharmaceuticals in the stream sediment, Principal Component Analysis (PCA) was used. The result of PCA showed, that in the stream sediment (depth 10-30 cm), Betaproteobacteria negatively correlated with triclosan and Clostridia negatively...

This thesis deals with the oxidative degradation of the active pharmaceutical substance ticagrelor, which is used together with acetylsalicylic acid as a prevention against atherothrombotic events in adult patients. In this thesis, oxidation was studied both in the traditional way using hydrogen peroxide and the new electrochemical approach. The oxidation was performed with a 3% solution of hydrogen peroxide at 50 řC in various solvents. An electrochemical method for the oxidation of ticagrelor was developed as part of the thesis. This method was then optimized to achieve the highest possible oxidation efficiency. The thesis also investigated the effect of excipients on the oxidation rate. Degradation products were evaluated using the ultra-high performance liquid chromatography. The structures of all the degradation products formed were identified using a QDA mass detector. Key words: UPLC, electrolysis, degradation studies, pharmaceuticals

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