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Environmental Fate of Chiral Pharmaceuticals: Determination, Degradation and Toxicity

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Environmental Fate of Chiral Pharmaceuticals: Determination, Degradation and Toxicity Chapter 1 Environmental Fate of Chiral Pharmaceuticals: Determination, Degradation and Toxicity Ana R. Ribeiro , Paula M. L. Castro , and Maria Elizabeth Tiritan Contents 1.1 Introduction – Basic Concepts of Chirality ...................................................................... 5 1.2 Chiral Pharmaceuticals ..................................................................................................... 8 1.3 Analytical Methods for Quantifi cation/Identifi cation of Chiral Pharmaceuticals in the Environment ................................................................................. 13 1.3.1 Chromatography .................................................................................................... 13 1.3.1.1 Indirect Methods ..................................................................................... 13 1.3.1.2 Direct Methods ....................................................................................... 14 1.3.2 Gas Chromatography (GC) .................................................................................... 15 1.3.3 High Performance Liquid Chromatography (HPLC) – Liquid Chromatography/Mass Spectrometry (LC/MS) .................................................... 15 1.3.3.1 Capillary Electro-Chromatography (CEC) ............................................. 16 1.3.3.2 Other Techniques .................................................................................... 23 1.3.4 Electrochemical Sensors and Biosensors............................................................... 24 1.4 Biotic and Abiotic Degradation and Removal Processes of Chiral Pharmaceuticals in the Environment ................................................................................. 24 1.4.1 Biodegradation of Non Steroid Anti-Infl ammatory Drugs (NSAIDs), Beta-Blockers and Antidepressants as Individual Enantiomers ............................ 25 1.5 Toxicity of Emergent Chiral Pharmaceuticals in Aquatic Organisms .............................. 30 1.6 Conclusions ....................................................................................................................... 36 References .................................................................................................................................. 37 A. R. Ribeiro Centro de Investigação em Ciências da Saúde (CICS) , Instituto Superior de Ciências da Saúde-Norte , Rua Central de Gandra, 1317 , 4585-116 , Gandra PRD , Portugal Centro de Biotecnologia e Química Fina (CBQF), Escola Superior de Biotecnologia , Universidade Católica Portuguesa , Porto , Portugal P. M. L. Castro Centro de Biotecnologia e Química Fina (CBQF), Escola Superior de Biotecnologia , Universidade Católica Portuguesa , Porto , Portugal E. Lichtfouse et al. (eds.), Environmental Chemistry for a Sustainable World: 3 Volume 2: Remediation of Air and Water Pollution , DOI 10.1007/978-94-007-2439-6_1, © Springer Science+Business Media B.V. 2012 4 A.R. Ribeiro et al. Abstract Pollution of the aquatic environment by pharmaceuticals is of major concern. Indeed pharmaceutical pollutants have several undesirable effects for many organisms, such as endocrine disruption and bacterium resistance. They are resis- tant to several degradation processes, making their removal diffi cult and slow. Pharmaceuticals reach the environment due to their ineffi cient removal by waste water treatment plants (WWTP), and by improper disposal of unused medicines. In aquatic environments pharmaceuticals reach concentrations at trace levels of ngL −1 – m gL−1 range. Many pharmaceutical pollutants are chiral. They occur in nature as a single enantiomer or as mixtures of the two enantiomers, which have different spatial confi guration and can thus be metabolized selectively. In spite of similar physical and chemical properties, enantiomers have different interactions with enzymes, receptors or other chiral molecules, leading to different biological response. Therefore they can affect living organisms in a different manner. The fate and effects of enantiomers of chiral pharmaceuticals in the environment are still largely unknown. Biodegradation and toxicity can be enantioselective, in contrast to abiotic degradation. Thus accurate methods to measure enantiomeric fractions in the environment are crucial to better understand the biodegradation process and to estimate toxicity of chiral pharmaceuticals. We review (1) general properties of chiral compounds, (2) current knowledge on chiral pharmaceuticals in the environment, (3) chiral analytical methods to deter- mine the enantiomers composition in environmental matrices, (4) degradation and removal processes of chiral pharmaceuticals in the environment and (5) their toxic- ity to aquatic organisms. The major analytical methods discussed are gas chroma- tography (GC), high performance liquid chromatography (HPLC), electrochemical sensors and biosensors. These chiral methods are crucial for the correct quantifi ca- tion of the enantiomers regarding that if an enantiomer with more or less toxic effects is preferentially degraded, the assessed exposure based on measurements of achiral methodologies would overestimate or underestimate ecotoxicity. The degra- dation and biodegradation is discussed using few examples of important therapeutic classes usually detected in the aquatic environment. Few examples of ecotoxicity studies are also given on the occurrence of enantiomers and their fate in the environ- ment which differs with regard to undesirable effects and to biochemical processes. M. E. Tiritan ( *) Centro de Investigação em Ciências da Saúde (CICS) , Instituto Superior de Ciências da Saúde-Norte , Rua Central de Gandra, 1317 , 4585-116 , Gandra PRD , Portugal Centro de Química Medicinal da Universidade de Porto (CEQUIMED-UP) , Porto , Portugal Instituto Superior de Ciências da Saúde-Norte , Rua Central de Gandra, 1317 , 4585-116 , Gandra PRD , Portugal e-mail: [email protected]; [email protected] 1 Environmental Fate of Chiral Pharmaceuticals: Determination, Degradation... 5 Keywords Chiral chromatography • Enantioselective • Biodegradation • Enantiomeric fraction • Enantioseparation • Racemates • Enantiomers • Chiral switching • Chiral analysis • Waste water treatment plant • Beta-blockers • Antidepressants • Non steroid anti-infl ammatory drugs • Enantiospecifi c toxicity • Chiral stationary phases • Fluoxetine • Propranolol • Atenolol • Ibuprofen • Naproxen • Chiral ecotoxicity 1.1 Introduction – Basic Concepts of Chirality Chiral compounds are substances with a similar chemical structure that, in general, confers them the same physical and chemical properties like melting point, solubility and reactivity. However they differ in the deviation of polarized light due to the dif- ferent spatial confi guration originated by planes, axis or centers of asymmetry given two nonsuperposable left-handed and right-handed mirror images compounds, called enantiomers. The planar chirality refers to a planar unit connected to an adja- cent part of the structure by a bond which results in restricted torsion avoiding the symmetry plane as in the monosubstituted paracyclophane (Fig. 1.1a ). When a set of ligands is held around an axis originates a spatial arrangement which is nonsuper- posable on its mirror image known as axial chirality. Such cases include ortho - substituted biphenyls and substituted allenes, a group of stereoisomers called atropoisomers which have a restricted rotation about a single bond, being the abso- lute confi guration called R or S preceded by an a ( aR or aS ) to distinguish them by other optical active compounds (Fig. 1.1b, c, d ) (Moss 1996 ; Santos et al. 2007 ) . The center chirality consists in a stereogenic center holding a set of four different substituents in a spatial arrangement which also origins two nonsuperposable left- handed and right-handed mirror image compounds (Fig. 1.2 ). The most common type of center chirality is a stereogenic carbon (Fig. 1.3 ), but other atoms such as sulphur or phosphorus can also be a stereogenic center (Fig. 1.4 ). Enantiomers can be identifi ed by the manner to rotate the polarized light, to the right (clockwise) are called dextrorotatory, (d) or (+), and to the left (counter clockwise) are denominated levorotatory, (l) or (−). Concerning their chemical confi guration relative to the spa- tial orientation of the substituent of the chiral center, enantiomers can be (R ) from the Latin rectus or ( S ) from the Latin sinister. The equimolar mixture of two enantiomers is a racemate or a racemic mixture and does not rotate the polarized light (Eliel and Wilen 1994 ) . Despite the similar thermodynamic properties in achi- ral medium, enantiomers normally have a different behaviour when the environ- ment is also chiral. Amino acids, carbohydrates, deoxyribose and ribose are chiral compounds which are the unity of important natural molecules such as proteins, glycoproteins, DNA and RNA, respectively (Müller and Kohler 2004 ; Hühnerfuss and Shah 2009 ) . As such, in biological processes, enzymes, receptors and other binding-molecules have the capacity to recognize enantiomers in a different way. The model that demonstrate the recognition of an enantiomer by a receptor due to their complementary confi guration is illustrated in Fig. 1.5 demonstrating that the 6 A.R. Ribeiro et al. aR b R1 R1 R2 R2 monosubstituted [2.2]paracyclophane ortho -substituted biphenyl c d R1 R3 R1 R4 CC CC C C R2 R4 R2 R3 (Sa )-allene (Ra )-allene Fig. 1.1 ( a ) Structure of monosubstituted [2.2] paracyclophane
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