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Validation of Oral Fluid As a Matrix for Drug Detection – Copyright Statement Validation of Oral Fluid as a Matrix for Drug Detection Eva Maria Reichardt A thesis submitted in partial fulfilment of the requirements of Bournemouth University for the degree of Doctor of Philosophy Validation of Oral Fluid as a Matrix for Drug Detection – Copyright Statement This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and due acknowledgement must always be made of the use of any material contained in, or derived from, this thesis. ii Validation of Oral Fluid as a Matrix for Drug Detection - Dedication This thesis is dedicated with great gratitude to my father Horst, my mother Conny, my sister Anne and my partner Tim for always encouraging me to be the best I can be. iii Validation of Oral Fluid as a Matrix for Drug Detection - Abstract Abstract Validation of Oral Fluid as a Matrix for Drug Detection Eva Maria Reichardt New testing procedures used as an aid for law enforcement are subject to intensive scrutiny in the courts. In recent years in workplace drug testing there has been a shift away from using traditional specimens (i.e urine) for drug testing and monitoring and a move to employing less invasive testing using oral fluid. Whilst it is now widely accepted that drugs can be detected in oral fluid and devices are now available to facilitate analysis of drugs in this matrix, our understanding of the behaviour of drugs in the mouth and oral secretions is far from complete. Since the introduction of oral fluid drug testing in the late 1990’s it has been observed that some drugs appear to be present at higher than expected concentrations, often at concentrations that would be fatal if they were in blood. Clearly some extra process is occurring in addition to drugs entering the oral fluid by simple blood and saliva partitioning. Little is really known about the physiology of drugs in the mouth and limited understanding of drug elimination via the mouth poses a problem to forensic toxicologists with the interpretation of analytical results in relation to an individual’s drug use or the possible effects that the drug may be exhibiting on that individual. The work described in this thesis is aimed at increasing our understanding of the factors and processes concerning the deposition, secretion and detection of drugs in oral fluid and enhancing our ability to interpret the results of analysis in this matrix. The objective of this study was to explore how high drug concentrations can be deposited in the mouth tissues and oral fluid together with other factors that may influence drug detection in order to assist with the interpretation of testing results. iv Validation of Oral Fluid as a Matrix for Drug Detection - Abstract To test the hypothesis that drug depots form within the mouth, preliminary screening methods in combination with confirmatory techniques such as GC-MS and LC- MS/MS were employed. The development of an immunohistochemical method was successfully demonstrated for the detection and visualisation of cocaine and opiates (heroin and morphine) in porcine and mouse tissue. The work undertaken in this thesis showed that elevated drug concentrations can be observed when drugs are consumed via oral administration either in form of an oral solution or smoking. Immunohistochemical analysis in combination with confirmatory techniques demonstrated that drugs such as cocaine and opioids can bind to oral tissue and be subsequently released over time, therefore has the potential to contribute to the drug concentration in oral fluid. Although this is not an issue under legislation that forbids the presence of drugs or as a check for drug compliance or abstinence, it must be considered in relation to the interpretation of results in more complex forensic cases. v Validation of Oral Fluid as a Matrix for Drug Detection – Table of Contents Table of Contents Abstract iv Table of Contents vi List of Figures xviii List of Tables xxxi Abbreviations xxxvi Acknowledgements xxxvii Chapter 1.0 - Background 1 1.1 Oral fluid 2 1.1.1 Composition of Oral Fluid 3 1.1.1.1 Saliva 3 1.1.1.1.1 Salivary Glands 4 1.1.1.1.2 Salivary pH 6 1.1.1.2 Lipids in oral fluid 6 1.1.1.3 Proteins in oral fluid 8 1.1.1.4 Electrolytes in oral fluid 10 1.1.2 Salivary flow rate 12 1.1.3 Drug entry into oral fluid 13 1.1.4 Oral fluid collection 15 1.1.5 Workplace drug testing 16 1.1.5.1 SAMHSA guidelines 16 1.1.5.2 UK workplace drug testing guidelines 17 1.1.5.2.1 Oral fluid collection guidelines 17 1.1.5.2.2 Laboratory confirmation guidelines 18 1.1.5.2.3 Quality control and assurance guidelines 18 vi Validation of Oral Fluid as a Matrix for Drug Detection – Table of Contents 1.1.5.2.4 European workplace drug testing guidelines 18 1.1.6 Oral Fluid in the UK legal system 18 1.1.6.1 Roadside Testing of Oral Fluid 19 1.1.6.1.1 Early legislation 19 1.1.6.1.2 Current legislation 19 1.1.7 Variation of drug concentrations in oral fluid - the problem! 20 1.1.7.1 Cocaine 21 1.1.7.1.1 Effects of cocaine administration 22 1.1.7.1.2 Cocaine Purity 22 1.1.7.1.3 Metabolism 23 1.1.7.1.4 Route of Administration 26 1.1.7.1.4.1 Intravenous injection 26 1.1.7.1.4.2 Nasal insufflation (snorting) 26 1.1.7.1.4.3 Oral ingestion 27 1.1.7.1.4.4 Smoking 28 1.1.7.1.5 Mechanism of action 29 1.1.7.1.6 Tissue disposition 30 1.1.7.1.7 Elimination of cocaine 31 1.1.7.1.8 Toxicity 32 1.1.7.1.9 Elevated cocaine concentrations in oral fluid 33 1.1.7.2 Heroin 34 1.1.7.2.1 Effects of heroin administration 34 1.1.7.2.2 Metabolism 35 1.1.7.2.3 Heroin Purity 38 1.1.7.2.4 Routes of Administration 38 1.1.7.2.4.1 Intravenous injection 38 1.1.7.2.4.2 Nasal insufflation (snorting) 38 vii Validation of Oral Fluid as a Matrix for Drug Detection – Table of Contents 1.1.7.2.4.3 Oral Ingestion 39 1.1.7.2.4.4 Smoking 39 1.1.7.2.5 Mechanisms of action 39 1.1.7.2.6 Tissue disposition 40 1.1.7.2.7 Elimination 41 1.1.7.2.8 Toxicity 42 1.1.7.2.9 Elevated heroin and metabolite concentrations in oral fluid 43 Chapter 2.0 - Aims and Objectives 45 2.1 Aims 45 2.2 Objectives 45 Chapter 3.0 - Investigation of the effects of common food and beverages on oral fluid drug detection 48 3.1 Introduction 48 3.1.1 Orasure Intercept collection system 49 3.1.2 AlereTM Certus collection system 50 3.2 Materials and Methods 52 3.2.1 Materials 53 3.2.2 Methods 53 3.2.2.1 Collection Methods 53 3.2.2.1.1 Collection Method Study 1 – Effects of a range of foods and beverage on oral fluid collection methods 53 3.2.2.1.2 Collection Method Study 2 - Effects of vinegar on oral fluid collection methods 55 3.2.2.2 Analytical Method 56 3.3 Results and Discussion 56 3.3.1 Study 1 - Effects of a range of foods and beverage on oral fluid collection methods 56 3.3.2 Study 2 - Effects of vinegar on oral fluid collection methods 63 3.4 Conclusion 72 viii Validation of Oral Fluid as a Matrix for Drug Detection – Table of Contents Chapter 4.0 - Concentrations of cocaine, benzoylecgonine and ecgonine methyl ester in oral fluid following the consumption of coca tea 74 4.1 Introduction 74 4.2 Materials and Methods 76 4.2.1 Materials 76 4.2.2 Methodology 76 4.2.2.1 Preparation of coca tea 76 4.2.2.2 Collection methods 77 4.2.2.3 Immunoassay 78 4.2.2.4 Solid Phase Extraction (SPE) 80 4.2.2.5 Liquid Chromatography – Mass Spectrometry 80 4.3 Results and Discussion 83 4.3.1 Immunoassay Results 83 4.3.2 LC-MS results 86 4.3.2.1 Cocaine 86 4.3.2.2 Benzoylecgonine 89 4.3.2.3 Ecgonine Methyl Ester (EME) 93 4.3.2.4 Summary of cocaine, benzoylecgonine and ecgonine methyl ester concentrations 97 4.3.3 Unexpected results 98 4.3.3.1 Cocaethylene 99 4.3.3.2 Anhydroecgonine Methyl Ester 100 4.3.3.3 Reanalysis of samples containing cocaethylene and anhydroecgonine methyl ester 101 4.3.3.3.1 Cocaethylene 101 4.3.3.3.2 Anhydroecgonine methyl ester 102 4.3.3.3.3 Summary of the results from the secondary analysis of samples to quantify anhydroecgonine methyl ester 108 ix Validation of Oral Fluid as a Matrix for Drug Detection – Table of Contents 4.4 Conclusion 113 Chapter 5.0 - Oral fluid opiate concentrations following oral consumption of Codeine Linctus® and Collis Browne’s® mixture 114 5.1 Introduction 114 5.2 Materials and Methods 116 5.2.1 Materials 116 5.2.1.1 Collection devices 116 5.2.1.2 Collis Browne’s® mixture 116 5.2.1.3 Codeine Linctus® 116 5.2.1.4 Methodology 117 5.2.1.5 Collection Procedure 117 5.2.1.5.1 Study 1 – Investigation into opiate oral fluid concentrations following the exposure to Collis Browne’s® mixture and Codeine Linctus® 117 5.2.1.5.2 Study 2- Investigation into opiate oral fluid concentrations following the exposure to Collis Browne’s® mixture and Codeine Linctus® with two different collection methods 117 5.2.1.6 Immunoassay (Study 2) 118 5.3 Results and Discussion 121 5.3.1 Study 1 - Investigation into concentrations of opiates in oral fluid following the exposure to Collis Browne’s® and Codeine Linctus® 121 5.3.1.1 Collis Browne’s® mixture 121 5.3.1.2 Codeine Linctus® 125 5.3.1.3 Summary of Study 1 128 5.3.2 Study 2 - Investigation into concentrations in oral fluid following the exposure to Collis Browne’s® and Codeine Linctus® with two different collection methods 130 5.3.2.1 Collis Browne’s® mixture 130 5.3.2.2 Codeine Linctus® 132 x Validation of Oral Fluid as a Matrix for Drug Detection – Table of Contents 5.4 Conclusion 134 Chapter 6.0 - Effect of microbleeding of the gums on oral fluid drug detection 136 6.1 Introduction 136 6.1.1 Microbleeding 136 6.1.2 Protein hormones in Saliva 137 6.2 Materials and Methods 138 6.2.1 Materials
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