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Download (6MB) https://theses.gla.ac.uk/ Theses Digitisation: https://www.gla.ac.uk/myglasgow/research/enlighten/theses/digitisation/ This is a digitised version of the original print thesis. Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] THE SOLID-PHASE EXTRACTION OF DRUGS FROM BIOLOGICAL FLUIDS. Thesis submitted in accordance with the requirements of the University of Glasgow for the degree of Doctor of Philosophy by Christine Mary Moore. BSc (Hons.), MSc., C.Chem. M.R.S.C. Department of Forensic Medicine and Science June 1989 © Christine Mary Moore, 1989. ProQuest Number: 10999233 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10999233 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 DEDICATION ACKNOWLEDGEMENTS I should like to thank the National Racing Greyhound Club for their financial support of this work. and the staff at the Veterinary School, Garscube, for their help in acquiring greyhound urine samples. I should also like to thank Dr. John Oliver for his supervision of this project and Professor Alan Watson for his encouragement during the last three years. Grateful thanks are extended to all the technical and secretarial staff, without exception, at the Department of Forensic Medicine and Science, particularly Mrs. Margaret Harrison and Mrs. Elizabeth Doherty for their tireless explanation of word-processing techniques as well as emotional support. The help and support of other colleagues and friends within the department, especially Anita Quye, is also gratefully acknowledged. I should particularly like to thank Dr. Ian Tebbett at the University of Illinois at Chicago, Ms. Shelley Kalita (Director) and Ms.Vicki Hoogervorst at the Illinois Racing Board, Elgin, and Dr. Barry Logan at the University of Tennessee, Memphis, for their co-operation in the final stages of this work. Finally, I should like to thank all my friends, particularly Jennifer Chalmers and Rosemary Porter, for their unwavering confidence in my ability. The most thanks, however. go to all the members of my family, especially my sister, Anne, but most of all, to my mother, without whose unfailing emotional and financial support none of this would have been possible. Thanks mum. ABBREVIATIONS Weights pg picogram ng nanogram ug microgram mg milligram g gram kg kilogram w/w weight/weight Volumes ul microlitre ml milliltre 1 litre v/v volume/volume Analytical Methods HPLC high pressure liquid chromatography GC gas chromatography LCMS liquid chromatography-mass spectrometry GCMS gas chromatography-mass spectrometry Extraction Methods L/L liquid/liquid SE solvent extraction SPE solid-phase extraction DE diatomaceous earth LIST OF TABLES Table Title Page 1. Retention times for diazepam and its 98 metabolites using HPLC. 2. Relationship between oxazepam concentration 101 and peak area using HPLC analysis. 3. Retention times for triazolam and its 104 metabolite using HPLC. 4. Relationship between triazolam and 105 1-hydroxy triazolam concentration and peak area using HPLC analysis. 5. Retention times for triazolam and its 107 metabolite using HPLC. 6. Reproducibility of HPLC analysis procedure 110 for benzodiazepines. 7. Retention times of benzodiazepines analysed 111 by HPLC. 8. Relationship between xylazine concentration 115 and peak area using HPLC analysis. 9. Retention times of compounds analysed by 117 HPLC/DAD spectroscopy. 10.a) Retention time of mazindol using various 124 eluent compositions. 10.b) Relationship between mazindol concentration and peak area using HPLC. 11. Maximum extraction of oxazepam from 128 aqueous solutions using C8 cartridges. 12. Determination of diazepam retention 130 using liquid scintillation counting. 13. Recoveries of oxazepam using C8 132 cartridges with elution solvents of decreasing polarity. 14. Extraction efficiency from C8 cartridges 135 for urine samples spiked with oxazepam. 15. Comparison of enzyme hydrolysed and 138 untreated urine samples containing oxazepam and extracted using C8 cartridges. vi . 16. Total oxazepam concentrations detected in 139 urine of racing greyhounds. 17 . Extraction efficiency for urine samples 143 spiked with triazolam and its metabolite using C8 cartridges. 18 . Improved extraction efficiency for urine 145 samples spiked with triazolam and its metabolite, with C8 cartridges using the same batch cartridges from the same supplier. 19 . Extraction efficiency for triazolam and 148 1-hydroxy triazolam from greyhound urine using C18 cartridges. 2 0 . Comparison of enzyme hydrolysed and 150 untreated urine samples containing triazolam and extracted using C8 cartridges. 2 1 . Greyhound urine samples (spiked with 153 xylazine) extracted using C8 cartridges. 22 . Mean extractions for xylazine from 155 greyhound urine using C18 columns. 23 . Amount of xylazine excreted determined by 158 C8 extraction procedures and HPLC analysis. 24 . Percentage recoveries of triazolam (lug/ml) 167 from spiked greyhound and human urine using polar sorbents. 25 .a) Extraction efficiency for triazolam and 173 1-hydroxy triazolam from greyhound urine using CN cartridges. 25 .b) Modified extraction procedure for 4-hydroxy triazolam. 26 . Amount of triazolam and its metabolites 177 determined in greyhound urine using CN cartridges. 27. Pharmacokinetic parameters for triazolam 182 and its metabolites in the urine of racing greyhounds. 28 . Amount of triazolam and its metabolites 186 determined in human urine using CN cartridges. 29 . Pharmacokinetic parameters for triazolam 189 and its metabolites in human urine. vii . 30. Extraction efficiency for flunitrazepam 192 and its metabolites from greyhound urine using CN cartridges. 31. Percentage recoveries of benzodiazepines 195 (0.5ug/ml) using cyanopropyl columns and acidic eluent. 32 . Extraction efficiency for xylazine from 199 greyhound urine using CN cartridges. 33 . Amount of xylazine excreted, determined 202 by CN extraction procedures and HPLC analysis. 34 . Pharmacokinetic parameters for xylazine 206 in the urine of racing greyhounds. 35 . Recovery data before and after evaporation 213 for basic drugs using cation exchange extraction. 36. Comparison of liguid/liquid, cation exchange 223 and diatomaceous earth extraction procedures. 37 . Drug recoveries from spiked greyhound urine. 231 38 . Recovery of mazindol from racehorse urine 237 using SCX columns. 39 . Mazindol levels in horse urine after 50mg 241 administration. 40. Pharmacokinetic parameters for mazindol in 245 the urine of racehorses. LIST OF FIGURES Figure Title Page 1. The metabolic routes of diazepam. 6 2 . The metabolic routes of triazolam. 8 3 . The metabolic routes of flunitrazepam. 11 4 . The structure of xylazine. 14 5 . The metabolic routes of mazindol. 17 6 . The extraction of drugs from a blood sample . 36 7 . Sorbent extraction cartridge. 38 8 . Routine screening procedure for drugs from 58 racehorse urine. 9 . Separation of diazepam from its major 99 metabolites using HPLC. 10. a) Separation of triazolam from 1-hydroxy 103 triazolam using HPLC - phosphate buffer. 10. b) Separation of triazolam from 1-hydroxy triazolam using HPLC - acetate buffer. 11. Separation of flunitrazepam from its 109 metabolites using HPLC. 12. Aqueous drug standard containing 11 basic 119 drugs analysed by HPLC/DAD. 13 . UV spectra of three opiates, three 121 phenothiazines and three benzodiazepines. 14. Primary interactions of a non-polar sorbent 126 15. Oxazepam extracted from greyhound urine - 136 3 hours after a single oral dose of diazepam using C8 columns and HPLC analysis. 16. Average excretion of oxazepam from 141 greyhound urine. 17. Primary interactions of a polar sorbent. 165 18. Triazolam and metabolites extracted from 178 greyhound urine - 3 hours after a single oral dose of triazolam - using CN columns and HPLC analysis. 19 . Average triazolam and metabolite excretion 179 from greyhound urine. 20 . Semi-logarithmic plot of triazolam and its 181 metabolites excreted from greyhound urine. 21. Triazolam and metabolites extracted from 185 human urine - 3 hours after a single oral dose of triazolam - using CN columns and HPLC analysis. 22 . Average triazolam and metabolite excretion 187 from human urine. 23 . Semi-logarithmic plot of triazolam and its 188 metabolites excreted from human urine. 24 . The structure of loprazolam. 196 25 . Xylazine extracted from greyhound urine - 201 2 hours after a single intramuscular dose - using CN columns and HPLC analysis. 26 . Average xylazine
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