A presença de resíduos de medicamentos antibacterianos em alimentos é um importante problema de saúde pública. Estas substâncias podem estar presentes nos alimentos em níveis inaceitáveis como resultados de práticas produtivas inadequadas. Devido a estas preocupações, são estabelecidos limites máximos de resíduos para estas substâncias (LMRs). No caso das sulfonamidas, este valor de LMR refere-se à soma do princípio ativo e de todos seus metabólitos. Neste trabalho, identificam-se e caracterizam-se metabólitos de sulfaquinoxalina (SQX) em diversas espécies animais. Dentro do processo investigativo, foram realizados estudos comparativos de métodos de extração, processos de validação e determinação de efeito de matriz. Foi elaborado e proposto um modelo para a priorização de fármacos baseado em análise de risco e discutiu-se o panorama atual da presença de resíduos de sulfonamidas em amostras ambientais. A investigação da formação de metabólitos de SQX in vitro e in vivo levaram à identificação de três compostos, dois deles ainda não descritos na literatura: N4-acetil-SQX, SQX-OH e N4-acetil-SQX-OH. O perfil de formação destes compostos em diversas espécies animais foi analisado e discutido. / The presence of antibacterial drugs residues in food is an important public health issue. These substances can be present in food at unacceptable levels due to inappropriate veterinary practices. Because of that, maximum residue levels (MRL) are established for these compounds. In the sulfonamide drugs case, this value corresponds to the sum of parent drug and their metabolites. In the present work, sulfaquinoxaline (SQX) metabolites were identified and characterized in several animal species. Inside that investigation process, several studies were developed about extraction methods, validation processes and matrix effects determination. A model for drugs residues prioritization based on risk analysis was proposed. Also, the state-of-art of sulfonamides residues analysis in environmental samples was discussed. The in vivo and in vitro investigation of SQX metabolites formation lead us to the identification of 3 compounds, 2 of them previously unreported: N4-acetyl-SQX, SQX-OH and N4-acetyl-SQX-OH. The formation profile of these compounds in several animal species was analyzed and discussed.

A presença de resíduos de medicamentos antibacterianos em alimentos é um importante problema de saúde pública. Estas substâncias podem estar presentes nos alimentos em níveis inaceitáveis como resultados de práticas produtivas inadequadas. Devido a estas preocupações, são estabelecidos limites máximos de resíduos para estas substâncias (LMRs). No caso das sulfonamidas, este valor de LMR refere-se à soma do princípio ativo e de todos seus metabólitos. Neste trabalho, identificam-se e caracterizam-se metabólitos de sulfaquinoxalina (SQX) em diversas espécies animais. Dentro do processo investigativo, foram realizados estudos comparativos de métodos de extração, processos de validação e determinação de efeito de matriz. Foi elaborado e proposto um modelo para a priorização de fármacos baseado em análise de risco e discutiu-se o panorama atual da presença de resíduos de sulfonamidas em amostras ambientais. A investigação da formação de metabólitos de SQX in vitro e in vivo levaram à identificação de três compostos, dois deles ainda não descritos na literatura: N4-acetil-SQX, SQX-OH e N4-acetil-SQX-OH. O perfil de formação destes compostos em diversas espécies animais foi analisado e discutido. / The presence of antibacterial drugs residues in food is an important public health issue. These substances can be present in food at unacceptable levels due to inappropriate veterinary practices. Because of that, maximum residue levels (MRL) are established for these compounds. In the sulfonamide drugs case, this value corresponds to the sum of parent drug and their metabolites. In the present work, sulfaquinoxaline (SQX) metabolites were identified and characterized in several animal species. Inside that investigation process, several studies were developed about extraction methods, validation processes and matrix effects determination. A model for drugs residues prioritization based on risk analysis was proposed. Also, the state-of-art of sulfonamides residues analysis in environmental samples was discussed. The in vivo and in vitro investigation of SQX metabolites formation lead us to the identification of 3 compounds, 2 of them previously unreported: N4-acetyl-SQX, SQX-OH and N4-acetyl-SQX-OH. The formation profile of these compounds in several animal species was analyzed and discussed.

A presença de resíduos de medicamentos antibacterianos em alimentos é um importante problema de saúde pública. Estas substâncias podem estar presentes nos alimentos em níveis inaceitáveis como resultados de práticas produtivas inadequadas. Devido a estas preocupações, são estabelecidos limites máximos de resíduos para estas substâncias (LMRs). No caso das sulfonamidas, este valor de LMR refere-se à soma do princípio ativo e de todos seus metabólitos. Neste trabalho, identificam-se e caracterizam-se metabólitos de sulfaquinoxalina (SQX) em diversas espécies animais. Dentro do processo investigativo, foram realizados estudos comparativos de métodos de extração, processos de validação e determinação de efeito de matriz. Foi elaborado e proposto um modelo para a priorização de fármacos baseado em análise de risco e discutiu-se o panorama atual da presença de resíduos de sulfonamidas em amostras ambientais. A investigação da formação de metabólitos de SQX in vitro e in vivo levaram à identificação de três compostos, dois deles ainda não descritos na literatura: N4-acetil-SQX, SQX-OH e N4-acetil-SQX-OH. O perfil de formação destes compostos em diversas espécies animais foi analisado e discutido. / The presence of antibacterial drugs residues in food is an important public health issue. These substances can be present in food at unacceptable levels due to inappropriate veterinary practices. Because of that, maximum residue levels (MRL) are established for these compounds. In the sulfonamide drugs case, this value corresponds to the sum of parent drug and their metabolites. In the present work, sulfaquinoxaline (SQX) metabolites were identified and characterized in several animal species. Inside that investigation process, several studies were developed about extraction methods, validation processes and matrix effects determination. A model for drugs residues prioritization based on risk analysis was proposed. Also, the state-of-art of sulfonamides residues analysis in environmental samples was discussed. The in vivo and in vitro investigation of SQX metabolites formation lead us to the identification of 3 compounds, 2 of them previously unreported: N4-acetyl-SQX, SQX-OH and N4-acetyl-SQX-OH. The formation profile of these compounds in several animal species was analyzed and discussed.

Cette étude a eu pour objectif de contribuer à une meilleure compréhension du comportement photochimique de certains micropolluants de type antibiotiques vétérinaires (sulfaquinoxaline, pyriméthamine) ou antibactérien (triclosan) en solution aqueuse et à la surface de la kaolinite, utilisée comme un modèle de sol.L’étude du comportement photochimique de la sulfaquinoxaline a été réalisée sous excitation à 254 nm et 365 nm. Dans tous les cas, une dégradation efficace est observée avec un rendement quantique qui dépend de la longueur d’onde d’excitation, du pH et la concentration d’oxygène dissous. De plus, la présence de l’oxygène moléculaire dans le milieu conduit à une inhibition partielle la photodégradation mettant en évidence l’implication partielle de l’état excité triplet. Ce dernier a pu être mis en évidence par photolyse laser nanoseconde à travers un transfert Triplet-Triplet (T-T) en employant le β-carotène comme accepteur. Sur le plan analytique, la phototransformation de la sulfaquinoxaline conduit à la formation d’un grand nombre de produits qui ont été identifiés par HPLC/ESI/MS/MS en identifiant les processus de fragmentation intervenant pour chaque molécule étudiée. L’étude a permis de montrer que les états excités singulet et triplet sont tout les deux impliqués dans la photodegradation et que les processus principaux intervenant sont la photohydrolyse, la désulfonation avec un réarrangement intramoléculaire, l'hydroxylation des motifs aromatiques et l'isomérisation selon un processus de type photo Fries.L’étude de la photoréactivité de la pyriméthamine a montré que la dégradation est plus efficace avec la forme neutre. Le rendement quantique a été évalué à environ 4,0x10-2 en milieu aéré et sous excitation à 254 nm. L’étude par photolyse laser a montré la formation intermédiaire de l’état excité triplet mais également de l’électron solvaté (absorption à 700 nm). Les processus de formation des photoproduits primaires sont la substitution de l’atome de chlore par un groupement hydroxyle ou par un atome d’hydrogène et l’hydroxylation du noyau aromatique.La dégradation des micropolluants à la surface du sol a pu être abordée en utilisant l’argile kaolinite comme support modèle. Ce système simplifié nous a permis d’étudier la photodégradation sous excitation en Suntest sur le plan cinétique et analytique. L’étude cinétique a été entreprise en fonction de différents paramètres tels que l’épaisseur de la kaolinite et la concentration initiale du substrat. Le premier effet nous a permis de montrer que pour des épaisseurs inférieures à 70 µm, la vitesse de diffusion du composé des zones sombres vers les zones irradiées est très rapide devant la photolyse et de ce fait, elle peut être négligée. Cet aspect a conduit à la détermination du rendement quantique de disparition à la surface de la kaolinite. Sur le plan analytique, les réactions observées sur l’argile sont différentes de celles observées en solution aqueuse. En effet, dans le cas de la sulfaquinoxaline, seul le produit de désulfonation est observé. Au contraire de la sulfaquinoxaline, l’étude complète de la molécule de triclosan a montré la formation de plusieurs produits et notamment des dimères ou des oligomères ce qui suggère la présence du substrat sous forme d’agrégats à la surface de l’argile. Afin de confirmer cette observation expérimentale, nous avons abordé une étude de modélisation par dynamique moléculaire. Celle-ci a donnée des informations très importantes sur l’organisation des molécules à la surface de la kaolinite. Ainsi, l’adsorption du triclosan fait intervenir d'importantes liaisons hydrogène avec la surface de la kaolinite. En présence de plusieurs molécules, la formation d’agrégats est gouvernée par une importante interaction entre les noyaux aromatiques de type π-stacking. / The study undertaken within this thesis concerns the photochemical behavior of the veterinary antibiotics sulfaquinoxaline and pyrimethamine, as well as the antimicrobial triclosan in aqueous solutions and at the surface of kaolin, used as a soil model.The photochemical study on sulfaquinoxaline was performed at 254 and 365 nm. In all cases, an efficient degradation was observed with a quantum yield that depends on the excitation wavelength, pH and the dissolved molecular oxygen concentration. Molecular oxygen acts as an inhibitor which reflects the involvement of the triplet excited state. Sulfaquinoxaline was clearly shown to be a photosensitizer of β-carotene via a triplet-triplet transfer process. From the analytical point of view, several photoproducts were generated and identified by using HPLC/ESI/MS/MS technique through a close analysis of the fragmentation processes. The byproducts that were formed via the singlet as well as the triplet excited states were mainly generated by photohydrolysis, desulfonation, hydroxylation and isomerisation reactions.The photochemical study of pyrimethamine indicates an efficient photoreactivity with the molecular form. The laser flash photolysis study reveals the implication of singlet and triplet excited states. The byproducts were mainly formed through the substitution of the chlorine atom by an hydroxyl group and the hydroxylation of the aromatic moiety.The photochemical study at the surface of soil was undertaken by using kaolin as a model support. Such simple system appears to be a guideline for precise kinetic and analytical studies. The former was performed as a function of several important parameters such as the layer thickness and the initial concentration of the substrate. The first parameter clearly indicates that for a thickness lower than 70 µm, the rate of diffusion is so fast that this process can be neglected when compared to the photochemical process. Thus, the first rate constant at the surface of kaolin was determined. Only the product of desulfonation was observed with sulfaquinoxaline while with triclosan, several byproducts were obtained such as dimers and oligomers suggesting the formation of aggregates at the surface of the solid support. In order to confirm this aspect, molecular dynamics studies were undertaken and indicate that the adsorption of triclosan mainly occurs at the surface of kaolin via hydrogen molecular bonds. The arrangement of the molecules in a cluster is governed by π-stacking type interactions between the aromatic moieties.