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A General Unknown Screening for Drugs and Toxic Compounds in Human Serum

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A General Unknown Screening for Drugs and Toxic Compounds in Human Serum A General Unknown Screening for Drugs and Toxic Compounds in Human Serum Thesis Submitted to the Faculty of Natural Sciences of the University of Basel, Switzerland for the Fulfilment of the Requirements for a Ph. D. Degree by Stefan Sturm from Biel (BE) Basel, 2005 Accepted by the faculty of natural sciences On proposal of Prof. Dr. Hauser Prof. Dr. Eberle Prof. Dr. Drewe Dr. Scholer Basel, 20. September 2005 Prof. Dr. Wirz Dean Table of Content 1. List of Abbreviations ......................................................................................5 2. Summary.........................................................................................................7 3. Introduction.....................................................................................................9 3.1. GENERAL UNKNOWN SCREENING ............................................................................................. 9 3.2. CHOICE OF SPECIMEN .............................................................................................................. 10 3.3. EXTRACTION TECHNIQUES ...................................................................................................... 10 3.3.1. Liquid-Liquid Extraction .................................................................................................. 10 3.3.2. Solid-Phase Extraction...................................................................................................... 11 3.4. CHROMATOGRAPHY ................................................................................................................ 13 3.4.1. HPLC-DAD System ......................................................................................................... 13 3.4.2. LC-MS System ................................................................................................................. 14 3.4.2.1. Interfaces.................................................................................................................................................... 14 3.4.2.2. Electrospray Ionization .............................................................................................................................. 15 3.4.2.3. Atmospheric Pressure Chemical Ionization ............................................................................................... 16 3.4.2.4. Ion Transfer Capillary and Ion Optics........................................................................................................ 17 3.4.2.5. Analysators and LC-MS Detection Modes................................................................................................. 17 3.4.2.6. Data-Dependent Acquisition (DDA).......................................................................................................... 19 3.4.2.7. Ion Detection System................................................................................................................................. 19 3.4.2.8. Vacuum System ......................................................................................................................................... 20 3.4.2.9. Adduct Formation ...................................................................................................................................... 20 3.4.3. Retention Time ................................................................................................................. 21 3.4.4. Chromatographic Conditions............................................................................................ 21 3.4.5. Influences of Biological Matrix........................................................................................ 21 3.4.5.1. Influences of Biological Matrix on Chromatographic Behaviour .............................................................. 21 3.4.5.2. Influences of Biological Matrix on Detection in HPLC............................................................................. 21 3.4.5.3. Influences of Biological Matrix on Detection in MS ................................................................................. 22 3.4.5.4. Evaluation of Matrix Effects in MS ........................................................................................................... 22 3.5. MASS SPECTRA LIBRARIES ...................................................................................................... 24 3.5.1. Single Mass Spectrometry ................................................................................................ 24 3.5.2. Tandem Mass Spectrometry ............................................................................................. 26 3.5.3. Data Dependent Acquisition............................................................................................. 27 3.5.4. Sample Preparation in a General Unknown Screening..................................................... 28 3.5.5. Chromatic Conditions in a General Unknown Screening................................................. 29 3.6. RESEARCH OBJECTIVE ............................................................................................................. 30 4. Materials and Methods..................................................................................31 4.1. GENERAL UNKNOWN SCREENING WITH HPLC....................................................................... 31 4.1.1. Materials ........................................................................................................................... 31 4.1.2. Sample and Buffer Preparation Procedures ...................................................................... 31 4.1.3. Extraction Procedure......................................................................................................... 31 4.1.4. HPLC-DAD Method......................................................................................................... 32 4.1.5. Extraction Recovery Yields.............................................................................................. 32 4.1.6. Identification and Semi-Quantification............................................................................. 32 4.1.7. Quantification ................................................................................................................... 33 4.2. GENERAL UNKNOWN SCREENING WITH MS ........................................................................... 34 4.2.1. Materials ........................................................................................................................... 34 4.2.2. Sample and Buffer Preparation Procedures ...................................................................... 34 4.2.3. Extraction Procedure......................................................................................................... 34 4.2.4. Chromatographic and Mass Spectral Conditions.............................................................. 35 4.2.5. Mass Spectral Library Building Conditions ..................................................................... 36 5. Results and Discussion .................................................................................38 5.1. SAMPLE PREPARATION AND CHROMATIC CONDITIONS FOR A GUS....................................... 38 3 Table of Content 5.1.1. Sample Preparation and Chromatic Conditions with HPLC............................................. 39 5.1.2. Sample Preparation and Chromatographic Conditions with LC-MS................................ 43 5.2. LIBRARY SCREENING AND QUANTIFICATION .......................................................................... 47 5.2.1. Identification with HPLC.................................................................................................. 47 5.2.2. A Semi-Quantitative Procedure with HPLC..................................................................... 48 5.2.3. Method Development ....................................................................................................... 50 5.2.4. Automatic Library Searching with LC-MS ...................................................................... 52 5.2.5. A Semi-Quantitative Procedure with LC-MS................................................................... 60 5.2.6. Comparison of LC-MS and HPLC-DAD ......................................................................... 74 5.3. CASE REPORTS ........................................................................................................................ 76 5.4. CONCLUSION ........................................................................................................................... 83 6. Appendix.......................................................................................................84 6.1. PROPOFOL ................................................................................................................................ 84 6.1.1. Introduction....................................................................................................................... 84 6.1.2. Materials and Methods...................................................................................................... 84 6.1.2.1. Reagents and Chemicals ............................................................................................................................ 84 6.1.2.2. Apparatus and Instrumental Conditions..................................................................................................... 84 6.1.2.3. Standard Preparation.................................................................................................................................
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