Please use this identifier to cite or link to this item: https://doi.org/10.48548/pubdata-433
Resource typeDissertation
Title(s)Pharmaceuticals in the Environment: Photolysis, Identification of Transformation Products - Environmental Risk Assessment for X-ray Contrast Media and Demonstrating the Feasibility of Designing Environmentally Biodegradable Derivatives Using the Example of Beta-Blockers
Alternative title(s)Arzneimittel in der Umwelt: Photolyse, Identifikation der Umformungsprodukte - Abschätzung des Umweltrisikos für Röntgen-Kontrastmittel und Nachweis der Möglichkeit von umweltbiologisch abbaubaren Derivaten am Beispiel von Beta-Blockern
DOI10.48548/pubdata-433
Handle20.500.14123/468
CreatorRastogi, Tushar
RefereeKümmerer, Klaus  0000-0003-2027-6488  118066382
Scheringer, Martin  1089322461
Ebinghaus, Ralf  0000-0003-0324-5524  1245897233
AdvisorKümmerer, Klaus  0000-0003-2027-6488  118066382
AbstractRecent studies have confirmed that the aquatic ecosystem is being polluted with an unknown cocktail of pharmaceuticals, their metabolites and/or their transformation products (TPs). Although individual pharmaceuticals are typically present at low concentrations, their continuous input into the aquatic ecosystem and their toxic and persistent presence are the major environmental concerns. Therefore, it is necessary to assess the environmental risk caused by these aquatic pollutants. Data on exposure are required for quantitative risk assessment of parent compounds and their transformation products (TPs) and/or metabolites. Such data are mostly missing, especially for TPs, because of the non-availability of TPs and very often metabolites for experimental testing. Therefore, the application of different in silico tools for qualitative risk assessment can be used. Also, the presence of these micro-pollutants (active pharmaceutical ingredients, APIs) in the aquatic cycle are increasingly seen as a challenge to the sustainable management of water resources worldwide due to ineffective effluent treatment and other measures for their input prevention. Given the poor prognosis for effluent treatment (‘end of the pipe’ approach) for input prevention of APIs in the environment, it is necessary to focus on the ‘beginning of the pipe’ strategy. The very beginning of the pipe is the molecules themselves. Therefore, novel approaches are needed like designing greener pharmaceuticals, i.e. better biodegradable ones in the aquatic environment after their release. Therefore, the present research work focused on two important topics a) assessment of the environmental risk associated with the presence of highly prescribed drugs and their TPs; b) demonstrating the feasibility of the ‘benign by design’ concept for designing biodegradable drug derivatives, which will have the better biodegradability in the environment after their release. The present thesis includes four research articles (1-4) which address these approaches. The first article is about the qualitative environmental risk assessment using the example of transformation products formed during photolysis (photo-TPs) of Diatrizoic acid (DIAT). Photolysis is the chemical reaction in which the compound is broken down by photons and often in combination with hydroxyl radicals. Photolysis is the most common abatement process of micro-pollutants in the environment. The qualitative risk assessment of DIAT and selected photo-TPs was performed by the PBT approach (i.e. Persistence, Bioaccumulation and Toxicity), using chemical analysis, experimental biodegradation test assays, QSAR models with several different toxicological endpoints and in silico read-across approaches. The second article addresses a tiered approach of implementing green and sustainable chemistry principles for theoretically designing better biodegradable and pharmacologically potent pharmaceuticals derivatives. Photodegradation process coupled with LC-MSn analysis, biodegradability testing and in silico tools such as quantitative structure-activity relationships (QSAR) analysis and molecular docking proved to be a very significant approach for the preliminary stages of designing chemical structures that would fit into the ´benign by design´ concept in the direction of green and sustainable pharmacy. Metoprolol (MTL) was used as an example. The third article was also the conceptual framework to get new drug derivatives that are biodegradable in order to tackle the global challenge of micro-pollutants in the aquatic cycle. This study increased the knowledge about the role of the attachment of certain functionalities to the parent drug molecule for its biodegradability whilst conserving drug-likeness. This approach was in the past a totally neglected issue within drug development. Atenolol (ATL), a selective β1 blocker, was selected as an example to incorporate the additional attribute such as biodegradability into its molecular structure while conserving its substructures responsible for β adrenergic receptor blocker activity. In fourth article, the concept of designing green biodegradable pharmaceuticals has been proven through expanded experimental analysis setting out from the experiences collected as described in article two and three. This study could be considered as a more extensive feasibility study of rational design of green drug derivatives. The non-selective β-blocker Propranolol (PPL) was used as an example. The risk assessment study (Article #1) contributes in enhancing the existing knowledge about the life cycle and behavior (fate) of pharmaceuticals with a special focus on photo-TPs which are generally formed during advanced effluent treatment and enter as such into the environment. Based on the obtained results, the application of the in silico tools for qualitative risk assessment analysis increased knowledge space about the environmental fate of TPs in case of their non-availability for experimental testing. The benign by design studies (Article #2-4) were based on the knowledge and experience collected during the work on DIAT. It demonstrated the feasibility of a novel approach of designing comparatively better degradable and pharmacological potent derivatives through the implementation of ´green chemistry´ principles. However, the present approach is in the juvenile stage and further knowledge has to be collected beforehand for the full implementation of this approach into drug development.

Neuere Studien haben bestätigt, dass das aquatische Ökosystem mit einem unbekannten Cocktail von Medikamenten, deren Metaboliten und/oder deren Transformationsprodukte (TPs) belastet wird. Obwohl einzelne Arzneimittel in der Regel nur in geringen Konzentrationen in der Umwelt vorhanden sind, sind ihr ständiger Eintrag in das aquatische Ökosystem, sowie ihre giftigen Eigenschaften und anhaltende Präsenz ein großes Umweltproblem. Daher ist es notwendig, das durch diese Wasserschadstoffe verursachte Umweltrisiko zu bewerten. Daten über die Exposition sind für die quantitive Risikobewertung von Ausgangssubstanzen und deren Transformationsprodukte (TPs) und /oder Metabolite erforderlich. Solche Daten fehlen meistens, insbesondere für TPs, aufgrund der Nichtverfügbarkeit von TPs und häufig der Metaboliten für experimentelle Tests. Deshalb kann die Anwendung verschiedener in silico Methoden für die qualitative Risikobewertung herangezogen werden. Die Anwesenheit dieser Mikroschadstoffe (pharmazeutische Wirkstoffe, APIs) im aquatischen Kreislauf wird zunehmend weltweit als Herausforderung für die nachhaltige Bewirtschaftung der Wasserressourcen aufgrund ineffektiver Abwasserbehandlung und anderer Maßnahmen zur Eingabe-Prävention gesehen. Angesichts der schlechten Prognose für die Abwasserbehandlung (´Ende der Leitung´-Ansatz) für die Eingabe-Prävention von APIs in die Umwelt ist es notwendig, sich auf die ´Anfang des Rohres´-Strategie zu konzentrieren, z.B durch die Fokussierung auf Verbesserung der untersuchten Moleküle. Daher sind neue Ansätze wie die Gestaltung ´grüner´ Arzneimittel erforderlich, d. h. Moleküle, die nach ihrer Freisetzung in die Umwelt besser biologisch abbaubar sind. Daher konzentriert sich die vorliegende Forschungsarbeit auf zwei wichtige Themen a) Beurteilung der Umweltrisiken durch häufig verordnete Medikamente und durch ihre Abbauprodukte; b) Vorführung der Machbarkeit des ´Benign by Design´ Konzeptes für die Gestaltung von biologisch abbaubaren Pharmazeutika-Derivaten, die eine verbesserte biologische Abbaubarkeit in der Umwelt nach ihrer Freisetzung haben. Die vorliegende Arbeit umfasst vier Forschungspublikationen (1-4), die diese Ansätze adressieren. Die Studien zur gezielten Entwicklung umweltfreundlicher Medikamente (Artikel # 2-4) wurden auf dem Wissen und der Erfahrung aus der Arbeit an DIAT aufgebaut. Sie demonstrierten die Machbarkeit und Chancen eines neuartigen Ansatzes der Gestaltung vergleichsweise besser abbaubarer und pharmakologisch aktiver Derivate durch die Umsetzung der Prinzipien der ´grünen Chemie´. Allerdings ist der vorliegende Ansatz im Anfangsstadium und das Wissen für die vollständige Umsetzung dieses Ansatzes in der Medikamentenentwicklung muss weiterhin vergrößert werden.
LanguageEnglish
Date of defense2015-05-20
Year of publication in PubData2015
Publishing typeFirst publication
Date issued2015-07-30
Creation contextResearch
Granting InstitutionLeuphana Universität Lüneburg
Published byMedien- und Informationszentrum, Leuphana Universität Lüneburg
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