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A Review of Synthetic Fentanyl Metabolism and the Metabolism of Select Synthetic Fentanyl Analogues

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A Review of Synthetic Fentanyl Metabolism and the Metabolism of Select Synthetic Fentanyl Analogues A review of synthetic fentanyl metabolism and the metabolism of select synthetic fentanyl analogues Gerard Lee A thesis submitted for the completion of a degree in Master of Forensic Science (Professional Practice) in The School of Veterinary and Life Sciences Murdoch University Supervisors: Associate Professor James Speers (Murdoch) Associate Professor Bob Mead (Murdoch) Semester 1, 2019 i Declaration I declare that this thesis does not contain any material submitted previously for the award of any other degree or diploma at any university or other tertiary institution. Furthermore, to the best of my knowledge, it does not contain any material previously published or written by another individual, except where due reference has been made in the text. Finally, I declare that all reported experimentations performed in this research were carried out by myself, except that any contribution by others, with whom I have worked is explicitly acknowledged. ii Acknowledgements I would like to thank my supervisor Bob Mead for his time guiding me and providing feedback on this endeavour. He has been a great help providing insights and advice from when I started university at Murdoch until now for which I am extremely grateful. To James Speers, thank you for helping me find a direction for this project when I started out. And finally, to my family and friends for their encouragement and support. iii Table of Contents Title page. ...............................................................................................................................I Declaration. ............................................................................................................................Ii Acknowledgements ................................................................................................................iii PART ONE Literature Review. ..................................................................................................................1-57 PART TWO Manuscript .............................................................................................................................58-87 iv v Part One: Literature Review A review of synthetic fentanyl metabolism and fragmentation patterns of synthetic fentanyl analogues 1 Table of Contents List of Figures ............................................................................................................................. 3 List of Tables .............................................................................................................................. 4 Abbreviations ............................................................................................................................. 4 Abstract ...................................................................................................................................... 5 Chapter 1: Introduction ............................................................................................................. 6 1.1. Fentanyl pharmacology and mechanism of action ...................................................... 9 1.2. Chemical structure of fentanyl and its derivatives ....................................................... 10 1.2.1. Acetylfentanyl, structure and history……………………………………………………………..12 1.2.2. Acrylfentanyl, structure and history……………………………………………………………….14 1.2.3. Butyrfentanyl, structure and history………………………………………………………………15 1.2.4. Furanylfentanyl, structure and history…………………………………………………………..17 1.3. Methods of identifying fentanyl analogues ................................................................. 19 1.4. Metabolism pathways of fentanyl and analogues ....................................................... 22 1.5. Fentanyl phase I and II metabolites ............................................................................. 23 Chapter 2: Discussion ................................................................................................................. 27 2.1. Metabolism of Acetylfentanyl ...................................................................................... 27 2.2. Metabolism of Acrylfentanyl ........................................................................................ 31 2.3. Metabolism of Butyrfentanyl ....................................................................................... 33 2.4. Metabolism of Furanylfentanyl .................................................................................... 36 2.5. Summary of fentanyl analogue metabolism ................................................................ 39 Chapter 3: Fentanyl analogue fragmentation patterns ............................................................. 41 3.1. Fragmentation patterns of fentanyl ............................................................................. 41 3.2. Fragmentation patterns of fentanyl analogues ............................................................ 44 3.3. Summary of fragmentation patterns............................................................................ 46 Chapter 4: Conclusion ................................................................................................................ 47 References ................................................................................................................................. 49 2 List of Figures Page Figure 1: Synthesis of fentanyl and acetylthiofentanyl ................................................................ 10 Figure 2: Possible modifications to the fentanyl molecule .......................................................... 12 Figure 3: Comparison of acetylfentanyl and fentanyl .................................................................. 13 Figure 4: Comparison of acrylfentanyl and fentanyl .................................................................... 14 Figure 5: Comparison of fentanyl and butyrfentanyl ................................................................... 16 Figure 6: Comparison of furanylfentanyl molecule to fentanyl ................................................... 18 Figure 7: Metabolic pathways and possible metabolites of fentanyl ........................................... 25 Figure 8: Proposed metabolic pathways of acetylfentanyl in human hepatocyte and human urine metabolites, with primary metabolites in enclosed boxes. ................................................ 29 Figure 9: Proposed metabolic pathways of acrylfentanyl in human hepatocyte and human urine metabolites, with major metabolites in enclosed boxes .................................................... 32 Figure 10: Proposed metabolism pathways of butyrfentanyl in vivo and in vitro ....................... 35 Figure 11: Proposed metabolite structures for furanylfentanyl................................................... 37 Figure 12: Proposed metabolic pathways of furanylfentanyl in human hepatocyte and human urine metabolites, with major metabolites in enclosed boxes .................................................... 38 Figure 13: Proposed fragmentation pathway schematic for fentanyl and associated 4-ANPP analogues ...................................................................................................................................... 42 Figure 14: Piperidine ion ............................................................................................................... 43 Figure 15: Product ion of the four fentanyl analogues generated by cleavage b/c ..................... 44 Figure 16: Product ion of the four fentanyl analogues generated by cleavage d ........................ 45 Figure 17: Proposed fragmentation pathways for fentanyl analogues ........................................ 47 3 List of Tables Page Table 1: Summary of the names, formula and mass-to-charge ratio of the investigated fentanyl analogues ........................................................................................................................ 30 Abbreviations EMCDDA European Monitoring Centre for Drugs and Drug Addiction GTP Guanine triphosphate GDP Guanine diphosphate cAMP Cyclic adenosine monophosphate ED50 Effective dose SWGDRUG Scientific Working Group for the Analysis of Seized Drugs GC-MS Gas chromatography-mass spectrometry LC-HRMS Liquid chromatography/high-resolution mass spectrometry LC-MS/MS Liquid chromatography tandem mass spectrometry m/z Mass to charge ratio LC-MS Liquid-chromatography mass spectrometry LC Liquid-chromatography ToF time-of-flight MS/MS Tandem mass spectrometry MRM Multiple reaction monitoring LC-QTOF Liquid chromatography quadrupole time of flight ESI Electrospray Ionisation CYP 3A4 Cytochrome P450 3A4 CYP 2D6 Cytochrome P450 2D6 HPLC-MS High performance liquid chromatography mass spectrometry iPS Induced pluripotent stem cells h-iPS-HEP Human induced pluripotent stem cell-derived hepatocytes h-PRM-HEP Human primary hepatocytes 4-ANPP 4-anilino-N-phenethyl-piperidine UHPLC Ultra-high-performance liquid chromatography QTOF Quadrupole time-of-flight EI-MS Electron ionisation mass spectrometry CID Collision-induced dissociation 4 Abstract Fentanyl is a fast acting, potent synthetic opioid. It is also used as a narcotic of abuse posing a life-threatening hazard to everyone that comes into contact with it. The illicit production of new fentanyl analogues creates challenges as new analytical approaches have to be developed in order to identify the new analogues and their metabolites. Further understanding of metabolites and metabolic pathways would therefore improve the ability to identify new
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