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ESI-MS Method for the Simultaneous Detection of Five Major Opium Alkaloids

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ESI-MS Method for the Simultaneous Detection of Five Major Opium Alkaloids Development and evaluation of an LC- ESI-MS method for the simultaneous detection of five major opium alkaloids M.G. Carlin PhD 2015 Development and evaluation of an LC-ESI- MS method for the simultaneous detection of five major opium alkaloids Michelle Groves Carlin A thesis submitted in partial fulfilment of the requirements of the University of Northumbria at Newcastle for the degree of Doctor of Philosophy Research undertaken in the Department of Applied Sciences, Faculty of Health & Life Sciences August 2015 Abstract The aim of this work was to establish an analytical method for the simultaneous detection of five major opium alkaloids in poppy seeds by liquid chromatography-electrospray ionisation-mass spectrometry (LC- ESI-MS). Once opium alkaloids were detected in poppy seeds, toxicological studies were carried out to establish if these compounds were detected in oral fluid (OF) of participants who ingested muffins containing poppy seeds. It is known that the ingestion of poppy seeds has caused positive opiate drug test results and much work has been reported in the scientific literature in the last 20 years. Researchers in the field have investigated alternatives to differentiate between heroin administration and that of other opiate drugs versus poppy seed ingestion. Most of the work which has been carried out relates to establishing illicit heroin use by examining biological matrices for the presence of acetylcodeine, thebaine, papaverine, noscapine and their associated metabolites. The research methodology consisted of establishing an LC-ESI-MS method for the simultaneous detection of five major opium alkaloids (morphine, codeine, thebaine, papaverine and noscapine). A deuterated internal standard (morphine-d3) was used for the quantitation of alkaloids in harvested poppy seeds and oral fluid samples. Due to technical difficulties, 3 LC-MS instruments were employed in this work. Electrospray ionisation was employed in all mass spectrometers but the analysers included an ion trap with octopole, a triple quadrupole and a hybrid quadrupole Orbitrap. Suitable extraction procedures were determined and harvested seeds purchased from a number of supermarkets were analysed for the presence of five alkaloid compounds using the LC-MS method. A small scale pilot study with 6 participants was carried out to establish if it was possible to fail an OF drug test for opiates after consuming poppy seed muffins. OF samples were collected post ingestion using Quantisal™ kits and the level of each of the opiates was monitored. The findings were that an LC-ESI-MS method was established for the simultaneous detection and quantitation of five major alkaloids. However, the method development process involved finding a solution to co-elution of morphine and codeine. The process also included resolving the issue of thebaine producing two peaks with identical mass spectra and separated by a difference of 6 minutes in retention time. Varying levels of alkaloids were identified in harvested poppy seeds: levels of these compounds differed considerably within and between batches of poppy seeds. These findings could be attributed to a number of factors, for example, where and how the plants were grown and methods of harvesting. Two poppy seed muffins were consumed as part of a toxicology study. Morphine was detected in the 5 minute sample in 5 out of the 6 participants with concentrations in OF of 0.5-0.8 ng mL-1; codeine was detected in 2 of the 6 participants at 1.5 and 2.6 ng mL-1. Thebaine, noscapine and papaverine were also detected in OF of a number of participants, which has not been previously reported in the literature. However, it should be noted that the values calculated are only estimated since the peak area ratios obtained were found to be less than the lowest concentration (10 ng mL-1) in the linear calibration range. In conclusion, an LC-ESI-MS method for the simultaneous detection and quantitation of five major opium alkaloids has been established and has been used to detect alkaloids in harvested poppy seeds and oral fluid samples. From a small pilot toxicology study, oral fluid results indicate that levels of morphine and codeine do not exceed the SAMSHA 40 ng mL-1 cut-off after ingestion of a realistic amount of poppy seeds contained within bakery products. i List of Contents Abstract……………………………………………………………………………………………………………………………….i List of Contents…………………………………………………………………………………………………………………..iii List of Figures……………………………………………………………………………………………………………………..vi List of Tables……………………………………………………………………………………………………………………….x List of Abbreviations....………………………………………………………………………………………………………xii Acknowledgements………………………………………………………………………………………………….………xiii Declaration………………………………………………………………………………………………………………….…..xiv 1. OPIUM AND OPIATES ....................................................................................................... 1 1.1. History of opium poppies ......................................................................................... 1 1.1.1. In the beginning…............................................................................................. 1 1.1.2. 10th – 12th centuries ......................................................................................... 1 1.1.3. Paracelsus ........................................................................................................ 2 1.1.4. The (very) political years .................................................................................. 3 1.1.5. The chemical years ........................................................................................... 5 1.1.6. The Opium Wars (1839-1842 and 1856-60) .................................................... 6 1.1.7. The discovery of diacetylmorphine .................................................................. 6 1.1.8. Modern uses of the opium poppy ................................................................... 9 1.2. Papaver somniferum L. ............................................................................................ 9 1.2.1. Opium, opiates and their uses ......................................................................... 9 1.2.2. Pharmaceutical industry ................................................................................ 12 1.2.3. Food industry ................................................................................................. 13 1.2.4. Opiates and abuse .......................................................................................... 15 1.3. Opium and opiates ................................................................................................. 16 1.4. Alkaloid biosynthesis in Papaver somniferum L. .................................................... 18 1.4.1. Biosynthesis of major opium alkaloids .......................................................... 18 1.5. Toxicology .............................................................................................................. 23 1.5.1. Toxicology of the opium alkaloids.................................................................. 23 1.5.2. Poppy seed ingestion versus heroin use ........................................................ 33 2. OPIATES IN ORAL FLUID ................................................................................................. 35 2.1. Biological matrices and drug testing ...................................................................... 35 ii 2.1.1. Saliva vs oral fluid ........................................................................................... 36 2.1.2. Pharmacokinetics of drugs in oral fluid.......................................................... 37 2.1.3. Challenges of using oral fluid in drug testing ................................................. 43 2.1.4. Extraction of drugs ......................................................................................... 44 2.1.5. Interpretation of oral fluid results ................................................................. 45 2.2. GC-MS versus LC-MS .............................................................................................. 46 2.3. Research aims ........................................................................................................ 47 3. LIQUID CHROMATOGRAPHY – MASS SPECTROMETRY (LC-MS) .................................... 48 3.1. LC-MS ..................................................................................................................... 48 3.1.1. Liquid chromatography .................................................................................. 48 3.1.2. Mass spectrometry ........................................................................................ 50 3.1.3. Mass spectrometry analysers ........................................................................ 53 3.2. Analytical method development and validation .................................................... 55 4. ESTABLISHING AN LC-MS TESTING METHOD FOR THE SIMULTANEOUS DETECTION OF THE FIVE MAJOR OPIUM ALKALOIDS ..................................................................................... 58 4.1. Experimental .......................................................................................................... 58 4.1.1. Chemicals and reagents ................................................................................. 58 4.1.2. Instrumentation ............................................................................................. 58 4.1.3. Analysis of results..........................................................................................
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