Enantioselective occurrence and fate of chiral drugs in the aqueous environment

Lead Research Organisation: University of Bath
Department Name: Chemistry

Abstract

Drugs are potentially hazardous biologically active emerging contaminants as many of them are ubiquitous and persistent with suspected or identified toxicity towards aquatic organisms. Additionally, due to their continuous introduction into the environment and synergistic effects through combined parallel action, even drugs of a low persistence might cause unwanted effects in the environment. Hundreds of tonnes of these compounds are dispensed in communities every year and subsequently enter the environment through wastewater. Several groups of drugs such as beta-blockers, antibiotics or analgesics have been studied before in the environment but surprisingly their chiral character has been overlooked by environmental researchers. More than half of the drugs currently in use are chiral compounds and many of those are distributed as racemates consisting of an equimolar mixture of two enantiomers. A chiral molecule has at least one chiral centre (usually asymmetric carbon) as a result of which it shows optical activity. It exists in the form of two enantiomers, being the non-superimposable mirror images of each other. Enantiomers have the same chemical formula and physicochemical properties but they differ in their optical activity and spatial arrangement. The enantiomers of chiral compounds differ in interactions with chiral environments such as enzymes in the body. Therefore in biological systems they can be recognised as two different substances that elicit different responses: one enantiomer of the same drug may produce the desired therapeutic activity, while the other may be inactive or even toxic. The ratio of active/inactive enantiomer of the chiral drug can change significantly after its administration, metabolism in and excretion from the body. It can be subsequently altered during biological wastewater treatment and when the drug is already present in the environment. This is because degradation of enantiomers can be stereo-specific and can in some cases lead to an increase in the drug's toxicity. Research in this area is important as with the ageing population in western countries and an increase in consumption levels in the developing world increasing quantities of drugs are entering the environment and, to date, studies of the prevalence and characteristics of these contaminants in the environment have been limited in scope. Furthermore, existing reports, due to their non-enantiospecific analytical methodology, do not tackle the problem of chirality of drugs, so these studies cannot unequivocally differentiate between biological (enantioselective) and abiotic (non-enantioselective) processes. Therefore this project aims to identify chiral drugs in the aqueous environment and to test the hypothesis that their distribution in the aqueous environment is stereoselective and that stereoselective mechanisms governing their fate are biological in nature. The hypothesis will be tested through a series of analyses of surface water samples in West Yorkshire (the River Calder), concentrating on densely populated areas where the environment has the greatest potential to be contaminated with drugs. Analysis of contamination will be undertaken taking account of local wastewater treatment activity, thus achieving a more accurate understanding of the risk associated with the presence of chiral drugs in the environment. To achieve this a multi-residue analytical methodology that will allow for simultaneous identification and quantification of trace concentrations (low ppt levels) of chiral drugs of abuse in environmental matrices will be established. Verification of the stereoselectivity of the degradation of chiral drugs in the aqueous environment after taking into consideration non-stereoselective abiotic (photochemical processes, hydrolysis, sorption) and stereoselective biological (microbial) variables will also be undertaken at the laboratory scale with the usage of microcosm protocol and model compounds.

Publications

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Bagnall, J., Malia, L., Lubben, A. And Kasprzyk-Hordern, B. (2012) The stereo-selective biodegradation of amphetamine and methamphetamine in river water using chiral-LC-QTOFMS in 8th Annual LC/MS/MS Workshop on Environmental Applications and Food Safety, 2012-07-01 - 2012-07-03, Barcelona

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Evans S (2017) Enantiomeric profiling of a chemically diverse mixture of chiral pharmaceuticals in urban water. in Environmental pollution (Barking, Essex : 1987)

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Kasprzyk-Hordern B (2012) Estimation of community-wide drugs use via stereoselective profiling of sewage. in The Science of the total environment

 
Description The overall aim of the project was to undertake enantiomeric profiling of chiral drugs in the aqueous environment and to test the hypothesis that their distribution in the aqueous environment is stereoselective and that stereoselective mechanisms governing their fate are biological in nature. The groups of chiral drugs studied in the aqueous environment and in river microcosms included: amphetamine-like compounds (amphetamine, methamphetamine, MDMA, MDEA), ephedrines, beta-blockers (propranolol, atenolol and metoprolol) and antidepressants (fluoxetine and venlafaxine).
Project outcomes are presented below:
1. Development of novel methodology for enantiomeric profiling of chiral drugs in aqueous environmental matrices. A novel multi-residue methodology for enantiomeric profiling of chiral drugs in different environmental matrices utilising for the first time high resolution QTOF MS was developed. This method allows for both target analysis and screening of unknowns and is of key importance if mechanisms of degradation are studied.
2. Verification of enantiomer-specific fate of chiral drugs in the UK aqueous environment. Enantiomeric profiling of chiral drugs of abuse in the environment has never been a subject of investigation before. It revealed the enantiomer-specific fate of all studied drugs. The extent of stereoselectivity depended on several parameters including: type of a chiral drug, wastewater treatment technology used and season.
3. Discovery of enantiomer-specific biotransformation of chiral drugs in river microcosms. Laboratory microcosm experiments undertaken for drugs of abuse proved, in the first ever study of this kind, the hypothesis that stereoselective mechanisms governing fate of chiral drugs of abuse are biological in nature. This ground-breaking project proved for the first time that chiral drugs of abuse are subject to enantiomer-specific processes occurring in the environment and that the enantiomeric composition of a chiral drug can change throughout its environmental cycle. Knowing that two enantiomers of the same chiral drug usually differ in potency and toxicity (e.g. S(+)-amphetamine has twice as high stimulant activity than R(_)-amphetamine), the very same chiral compound might have different activity/toxicity at different stages of its environmental life cycle, which will depend on its origin and exposure to environmental factors. The above is of critical significance in the environmental risk assessment of pharmacologically active compounds, which currently does not take into account enantiomerism of pollutants and potentially leads to a significant under or overestimation of toxicity of chiral drugs.
Exploitation Route The developed analytical methods will be of use to environmental scientists and those interested in the analysis of chiral pharmaceuticals and illicit drugs. These beneficiaries will include toxicologists and those involved in the study of pharmacokinetics and pharmacodynamics of chiral drugs in the human body and forensic scientists because knowledge of enantiomeric composition of several illicit drugs, such as for example amphetamines, is an indication of their legal and illicit usage. This methodology will provide a comprehensive basis for the analysis of chiral drugs, greatly facilitating future research activity in this area. The methods can be also applied in toxicity studies of chiral drugs of abuse in the environment. Currently ecotoxicity of drugs is undertaken for racemic mixtures of chiral environmental pollutants and therefore is inaccurate as chiral drugs usually do not exist in the form of racemic mixtures in the environment as a result of their stereoselective metabolism in the body as well as biological degradation during wastewater treatment and in the environment. These methods will therefore be very useful for environmental toxicologists working in this field.
There is minimal, if any, understanding of the fate of chiral drugs in the aqueous environment, and this research broke new ground in significantly adding to the current body of knowledge. This understanding of stereoselectivity of drugs distribution in the environment will, in the longer term, be vital in making effective decisions regarding environmental risk, and will therefore benefit those government agencies responsible for the formulation and implementation of environmental policy, such as DEFRA and the Environment Agency. In the light of the research, statutory agencies and legislators will be therefore in a better position to make judgments regarding the restriction of specific pharmaceuticals which may negatively impact on human health and the wider aqueous environment. In addition, there may be grounds for legislative, procedural or policy changes in the area of water and wastewater treatment.
Sectors Chemicals,Environment,Pharmaceuticals and Medical Biotechnology

URL http://people.bath.ac.uk/bkh20/NEI0005341.htm
 
Description This research project provided advances in understanding of environmental transformation mechanisms of chiral drugs in the environment and opened a new area of research directed at stereoisomerism of chiral drugs in the environment. The phenomenon of chirality is of critical importance in assessing the possible risk chiral drugs might pose to human health and the environment. With a growing population and changing climate limiting accessibility of clean water and forcing new solutions based on water reuse, an understanding of stereoselective pathways of chiral drugs in the environment is vital to provide safe sustainable water resource management solutions for future generations. Outcomes of the projects were used to inform new procedures utilized in the newly-emerging interdisciplinary field of wastewater-based epidemiology which aims to provide an integrated approach towards public health monitoring at a community level based on innovative epidemiology techniques.
First Year Of Impact 2012
Sector Chemicals,Environment,Pharmaceuticals and Medical Biotechnology
Impact Types Policy & public services

 
Description DTG Directed, Stereochemistry of antimicrobial agents in urban water cycle and its impacts upon the evolution of antimicrobial resistance
Amount £89,114 (GBP)
Funding ID NE/R008094/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 10/2018 
End 09/2022
 
Description EPSRC, Project title: The fate of antimicrobials in urban wastewater and its role in the development of antimicrobial resistance
Amount £23,500 (GBP)
Funding ID 1789298 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 12/2019
 
Description EU Marie Curie Intra-European Fellowships
Amount £260,000 (GBP)
Funding ID 629015 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2014 
End 03/2016
 
Description Impact of stereochemistry of antimicrobial agents on their environmental fate, biological potency and the emergence of resistance
Amount £161,599 (GBP)
Funding ID NE/N019261/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2016 
End 03/2018
 
Description Industrial CASE Studentships
Amount £83,515 (GBP)
Funding ID NE/L009579/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2018
 
Description Marie Curie ITN
Amount € 4,200,000 (EUR)
Funding ID 317205 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2012 
End 09/2016
 
Description Research Project Grants
Amount £225,000 (GBP)
Funding ID RPG-2013-297 
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start 08/2014 
End 07/2017
 
Title New analytical methods for the analysis of chiral drugs at enantiomeric level 
Description New analytical methods utilising chiral liquid chromatography and mass spectrometry were developed to allow enantiomeric profiling of chiral pharmacologically active compounds in environmental matrices. 
Type Of Material Improvements to research infrastructure 
Year Produced 2012 
Provided To Others? Yes  
Impact New methods allowed for studies of chiral pharmacologically active compounds in the environment and during wastewater treatment. They were fundamental in testing the hypothesis that two enantiomers of the same chiral drug, due to their different interactions with biological systems, should be recognised in environmental studies as two different substances that can elicit different responses potentially leading to changes in environmental fate and ecotoxicity of the drug. The methods were also utilized in the newly emerging, interdisciplinary field of wastewater-based epidemiology to study community-wide health. 
URL http://www.sciencedirect.com/science/article/pii/S0021967312008783
 
Description Collaboration with Astra Zeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution PhD studentship: expertise, facilities, co-funded by EPSRC
Collaborator Contribution PhD studentship: expertise, financial contribution
Impact Excellent proof-of concept results, presentations.
Start Year 2016
 
Description Collaboration with Environment Agency 
Organisation Environment Agency
Country United Kingdom 
Sector Public 
PI Contribution Collaboration within NE/N019261/1 project entitled: 'Impact of stereochemistry of antimicrobial agents on their environmental fate, biological potency and the emergence of resistance'
Collaborator Contribution Collaboration within NE/N019261/1 project entitled: 'Impact of stereochemistry of antimicrobial agents on their environmental fate, biological potency and the emergence of resistance'
Impact Ongoing
Start Year 2016
 
Description Collaboration with Wessex Water 
Organisation Wessex Water
Country United Kingdom 
Sector Private 
PI Contribution expertise, equipment, facilities
Collaborator Contribution expertise, equipment, facilities
Impact Several, including academic papers: Petrie, B., Proctor, K., Youdan, J., Barden, R. and Kasprzyk-hordern, B., 2017. Critical evaluation of monitoring strategy for the multi-residue determination of 90 chiral and achiral micropollutants in effluent wastewater. Science of the Total Environment, 579, pp. 569-578. Petrie, B., Gravell, A., Mills, G. A., Youdan, J., Barden, R. and Kasprzyk-Hordern, B., 2016. In situ calibration of a new chemcatcher configuration for the determination of polar organic micropollutants in wastewater effluent. Environmental Science & Technology, 50 (17), pp. 9469-9478. Petrie, B., Youdan, J., Barden, R. and Kasprzyk-Hordern, B., 2016. A new framework to diagnose the direct disposal of prescribed drugs in wastewater - a case study of the antidepressant fluoxetine. Environmental Science & Technology, 50 (7), pp. 3781-3789. Petrie, B., Youdan, J., Barden, R. and Kasprzyk-Hordern, B., 2016. Multi-residue analysis of 90 emerging contaminants in liquid and solid environmental matrices by ultra-high-performance liquid chromatography tandem mass spectrometry. Journal of Chromatography A, 1431, pp. 64-78. Petrie, B., Barden, R. and Kasprzyk-Hordern, B., 2015. A review on emerging contaminants in wastewaters and the environment:current knowledge, understudied areas and recommendations for future monitoring. Water Research, 72, pp. 3-27.
Start Year 2012
 
Description 3. Cartwright, N and Kasprzyk-Hordern, B. To understand the risks to the environment from chemicals, , Environment Agency meeting 'Working Together for a Better Environment', Bristol, 21st February 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Talk on collaboration between University of Bath, Wessex Water and Environment Agency
Year(s) Of Engagement Activity 2017
URL https://www.instituteofwater.org.uk/events-info/613/
 
Description Innovation through partnership working, DEFRA, London 15th November 2016. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Talk at DEFRA WQ Team away day
Year(s) Of Engagement Activity 2016
 
Description Kasprzyk-Hordern, B. ,'Water and you: green, grey and you', Pint-of-Science Festival, Bath, 2014-05-19 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Several people attended the meeting

Positive feedback
Year(s) Of Engagement Activity 2014
 
Description Kasprzyk-Hordern, B., 'Divining human health through urban wastewater profiling', Bath Science Café, Bath, 2014-09-08 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact >40 people attended the talk, which stimulated questions and discussions afterwards

Positive feedback from the audience
Year(s) Of Engagement Activity 2014
 
Description Kasprzyk-Hordern, B., 'Testing urban water for community-wide public health assessment', CCAF Symposium 'The alchemy of what we swallow', 2014-09-09, Bath 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Approximately 100 people attended

Positive feedback
Year(s) Of Engagement Activity 2014
 
Description Kasprzyk-Hordern, B., 2014. Urban water cycle: environmental and health perspectives, STEM CPD Day, 2014-06-18, Bath 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Around 100 pupils attended the talk

Positive feedback
Year(s) Of Engagement Activity 2014
 
Description Talk by B. Kasprzyk-Hordern, 'Lessons learned from the SewProf Project and beyond', Global Consortium for Sustainability Outcomes, Workshop 2019, River Room, King's College London, Strand Campus, WC2R 2LS London, United Kingdom 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk by B. Kasprzyk-Hordern, 'Lessons learned from the SewProf Project and beyond', Global Consortium for Sustainability Outcomes, Workshop 2019, River Room, King's College London, Strand Campus, WC2R 2LS London, United Kingdom (invited talk)
Year(s) Of Engagement Activity 2019
 
Description Talk by B. Kasprzyk-Hordern, 'Urban water fingerprinting for environmental and public health assessmen', Kwaluzu-Natal University, Durban, 1st of February 2019, South Africa 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Talk by B. Kasprzyk-Hordern, 'Urban water fingerprinting for environmental and public health assessmen', Kwaluzu-Natal University, Durban, 1st of February 2019, South Africa (invited talk)
Year(s) Of Engagement Activity 2019
 
Description Talk by Kasprzyk-Hordern 'Antimicrobials in water cycle: Research gaps', Israel-UK Synergy programme grant symposium and workshop, 25th and 26th April 2018:"One Health: antimicrobial resistance from mechanisms to interdisciplinary solutions" The Institute of Microbiology and Infection, University of Birmingham 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Kasprzyk-Hordern, B., Castrignano E, Edler, F, 'Antimicrobials in water cycle: Research gaps', Israel-UK Synergy programme grant symposium and workshop, 25th and 26th April 2018:"One Health: antimicrobial resistance from mechanisms to interdisciplinary solutions" The Institute of Microbiology and Infection, University of Birmingham (invited talk)
Year(s) Of Engagement Activity 2018
 
Description Talk by Kasprzyk-Hordern, 'Urban water fingerprinting to inform the state of the environment and public health', University College London Chemical & Physical Society Guest Lecturer 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact B. Kasprzyk-Hordern, 'Urban water fingerprinting to inform the state of the environment and public health', University College London Chemical & Physical Society Guest Lecturer 16th October 2018 (invited talk)
Year(s) Of Engagement Activity 2018
 
Description Talk by Kasprzyk-Hordern, B., What's Your water telling you? Urban water profiling inform the state of the environment and public health, RSC Event, Bristol, 13th Feb 2018, University of the West of England 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Kasprzyk-Hordern, B., What's Your water telling you? Urban water profiling inform the state of the environment and public health, RSC Event, Bristol, 13th Feb 2018, University of the West of England (invited talk)
Year(s) Of Engagement Activity 2018
 
Description Urban water profiling for community-wide public health and environmental risk assessment, University of Bath Minerva series, 3rd of May 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact talk
Year(s) Of Engagement Activity 2016