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The Detection of Non-Steroidal Anti-Inflammatory Drugs in Keratinous Matrices

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The Detection of Non-Steroidal Anti-Inflammatory Drugs in Keratinous Matrices ANGLIA RUSKIN UNIVERSITY THE DETECTION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN KERATINOUS MATRICES ALIX GARTH-GREEVES A Thesis in partial fulfilment of the requirements of Anglia Ruskin University for the degree of Doctor of Philosophy Submitted: June 2016 ACKNOWLEDGEMENTS Firstly, I extend my gratitude to the Faculty of Science and Technology at Anglia Ruskin University. This research would not have been possible without their funding and continued support from the department of Biomedical and Forensic Sciences. I would like to personally thank my director of studies Dr Sarah Hall for her unending support throughout my studies. You have provided great advice and words of wisdom. To my second supervisor Dr Lata Gautam, thank you for your valuable feedback but whole heartedly, a thank you for lending an open ear and a constant smile. Both of you have made me into the researcher I am today. A thank you to Dr Nancy Harrison for your support and confidence boost when needed the most. Extended gratitude to my advisor Dr Ngaio Richards of whom this project could not have been without. You provided the foundations to this research area and I will be eternally grateful to all that you have done. To the wonderful Lisa Scott-Donkin, thank you for putting some “paella” into my writing and helping with those I’s before e’s. You really are amazing at what you do and I cannot thank you enough for your relentless support. To my marvellous parents, your unconditional love has kept me going throughout the ups and downs, thank you for being all together fabulous parents. You have always been my inspiration and source of encouragement, thank you for always believing in me. I also want to thank my sister for her constant words of positivity, being my rock and giving me two beautiful nieces of whom I hope one day I can pass on my knowledge. To all my fellow students, past and present, I express my gratitude for all the wonderful conversations and shared ideas. I would like to extend appreciation to all my friends and lovely in-laws, you have shared in my journey and in doing so have been a constant source of support and encouragement. A special mention to Joanne Hooson and Kevin Bright for their technical help, and to everyone in the office for going beyond the call of duty. To Reverend Ron, Val and all those at St Pauls, thank you for all the prayers and support. Finally, but by no means least, I would like to express my appreciation to my beloved husband, Simon. You have been my most constant source of unenviable support. Thank you for your enduring love, for believing in me long after I lost belief in myself, for all the times you have simply put it, “you can do this” and sharing in my aspiration. You have shared in sleepless nights, offered advice when no one was around and have always encouraged a positive balance between social and academic life. So on our first year of marriage I dedicate this thesis to you, after all it is paper. i ANGLIA RUSKIN UNIVERSITY ABSTRACT FACULTY OF SCIENCE AND TECHNOLOGY DOCTOR OF PHILOSOPHY THE DETECTION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN KERATINOUS MATRICES ALIX GARTH-GREEVES JUNE 2016 The problems of non-steroidal anti-inflammatory drugs (NSAIDs) as environmental contaminants is an area of concern. NSAIDs are heavily relied upon to treat pain and inflammation. With such prevalence, these compounds are now entering the environment via many routes, such as water discharge and contaminated food. This results in subsequent exposure and effects on various animal species. One such example is diclofenac, which was associated with the extinction of Gyps vultures in Asia. The detection of diclofenac was based on post-mortem samples i.e. after a large decline in populations. In this research non-invasive samples i.e hairs and feathers are analysed pre-mortality as a preventive measure for early detection. A simultaneous liquid chromatography-mass spectrometry (LC-MS) method for detection of eighteen compounds, either of known toxicological effects or future threat (NSAIDs - aceclofenac, carprofen, diclofenac, flunixin, ketoprofen, mefenamic acid, meloxicam, nimesulide, phenylbutazone, piroxicam and suxibuzone; metabolites - oxyphenylbutazone, 3-hydroxymethyl mefenamic acid, 4-hydroxydiclofenac, 4- hydroxynimesulide, 5-carboxymeloxicam, 5-hydroxyflunixin and 5-hydroxypiroxicam) has been developed and validated. A newly optimised sample preparation method was applied to hairs/feathers. Precision of the analytical method was within 10% relative standard deviations for the majority of compounds. Recoveries averaged 83% and limits of detection (LOD) ranged 0.01 to 0.2µg/g. For diclofenac, flunixin, mefenamic acid, oxyphenylbutazone, piroxicam and 5-hydroxyflunixin, LODs were lower than previously reported. Various animal hairs/feathers were analysed (n=20) and in two samples piroxicam and phenylbutazone were individually detected, at 1.2µg/g ± 0.002 and 1.8µg/g ± 0.011 respectively. The LC-MS method reported here has been validated for the first time using animal hair/feather samples. This range of NSAIDs and metabolites have never been reported before. LODs and LOQs of metabolites are reported for the first time. The detection of piroxicam and phenylbutazone in feathers highlights the viability of testing keratinous matrices. Keywords: NSAIDs, diclofenac, liquid chromatography-mass spectrometry, feathers, non-invasive ii TABLE OF CONTENTS ACKNOWLEDGEMENTS _________________________________________ i ABSTRACT ____________________________________________________ ii TABLE OF CONTENTS _________________________________________ iii LIST OF TABLES ______________________________________________ xi LIST OF ABBREVIATIONS______________________________________ xiii LIST OF APPENDICES _________________________________________ xvii COPYRIGHT DECLARATION ___________________________________ xviii CHAPTER 1: NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND THEIR PRESENCE, DETECTION AND IMPACT IN THE ENVIRONMENT _________ 1 1.1 RESEARCH RATIONALE _________________________________________ 1 1.1.1 Importance of developing new detection methods and alternative samples 4 1.2 THE VULTURE CRISIS AND THE ROLE OF NSAIDS ___________________ 5 1.2.1 Reported decline in vulture populations, early proposals _______________ 5 1.2.2 The breakthrough of the cause of vulture mass mortality ______________ 6 1.2.3 Phasing out the use of diclofenac ________________________________ 8 1.2.4 Ecological implications of vulture crisis ___________________________ 10 1.3 AN OVERVIEW OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) ________________________________________________________ 11 1.3.1 The definition and uses of NSAIDs in human and veterinary medicine ___ 11 1.3.2 Current NSAIDs known to be of threat ____________________________ 12 1.3.3 NSAIDs used the in this study __________________________________ 14 1.3.4 The chemical properties and structures of NSAIDs __________________ 15 1.3.5 Modes of administration _______________________________________ 21 1.3.6 Mechanism of action in the body ________________________________ 21 1.3.7 NSAIDs metabolism __________________________________________ 23 1.3.7.1 Metabolites to be detected in this research _____________________ 25 1.4 NON-INVASIVE SAMPLES _______________________________________ 34 1.4.1 The incorporation of NSAIDs and their metabolites in hair ____________ 34 1.4.2 History and advantages of hair analysis___________________________ 35 1.4.3 Feathers and the incorporation of analytes ________________________ 37 1.4.3.1 The selection of optimal feathers for analysis ___________________ 38 iii 1.5 THE ANALYTICAL TECHNIQUES EMPLOYED IN THIS RESEARCH _____ 39 1.5.1 Review of use of analytical techniques ___________________________ 39 1.5.2 LC-MS in comparison to other available techniques _________________ 40 1.5.3 Liquid Chromatography with Mass Spectrometry ____________________ 41 1.5.3.1 Electrospray ionisation interface _____________________________ 44 1.5.3.2 The quadrupole mass analyser ______________________________ 45 1.6 DEVELOPMENT AND VALIDATION OF AN ANALYTICAL METHOD _____ 46 1.6.1 Selection of NSAIDs and internal standards _______________________ 47 1.6.2 Method optimisation __________________________________________ 48 1.6.2.1 The Plate Theory of chromatography – column efficiency __________ 48 1.6.2.2 The Rate Theory of chromatography __________________________ 50 1.6.2.3 Column selection _________________________________________ 52 1.6.2.4 Capacity factor ___________________________________________ 53 1.6.2.5 Selectivity_______________________________________________ 54 1.6.2.6 Resolution ______________________________________________ 54 1.6.2.7 Peak asymmetry _________________________________________ 55 1.6.2.8 Solvent and mobile phase selection __________________________ 55 1.6.2.9 Injection volumes _________________________________________ 57 1.6.3 Identification of NSAIDs and diagnostic ions _______________________ 58 1.6.4 Stability ____________________________________________________ 58 1.6.5 Precision and Accuracy _______________________________________ 59 1.6.6 Linear range ________________________________________________ 59 1.6.7 Limits of Detection (LOD) and Limits of Quantification (LOQ) __________ 60 1.7 RESEARCH AIMS ______________________________________________ 60 CHAPTER 2: METHODOLOGY ___________________________________ 62 2.1 CHEMICALS AND REAGENTS ____________________________________ 62 2.2 STANDARDS PREPARATION ____________________________________ 62 2.2.1
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