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Download (7MB) 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 Development of HPLC Methods for the Determination of Methotrexate and Doxorubicin Metabolites and their Application to Clinical Studies. Yahya Yahya Zeki Farid BSc PhD University of Glasgow Department of Pathological Biochemistry Faculty of Medicine JUNE 1983 X s. HERON LTD 5 QUEENS CRESCENT ST. GEORGES CROSS GLASGOW 041 332 1883 ProQuest Number: 10646152 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. uesL ProQuest 10646152 Published by ProQuest LLO (2017). 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 LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 48106- 1346 'Thesis Cop^CL. GLASGOW UNIVERSITY LIBRARY ABBREVIATIONS ADR Doxorubicin ADRol Doxorubicinol ADRone Doxorubicin Aglycone amu Atomic Mass Unit AUC Area Under Curve Cl Clearance Clm Metabolic Clearance CIr Renal Clearance Crcl Creatinine Clearance CV Coefficient Variation DAMPA 4-Amino NiO-methylpteroic Acid DAÜN Daunorubicin DHFR Dihydrofolic Acid Reductase F Absorption Factor fe Fraction of Drug Excreted Unchanged h Reduced Height Plate HPLC High Performance Liquid Chromatography IM Intramuscular IS Internal Standard IT Intrathecal IV Intravenous k' Capacity Ratio Kel Serum Elimination Rate Constant M+ Mass Ion MTX Methotrexate MTXGi Methotrexate Diglutamate MTXG2 Methotrexate Triglutamate m/z Mass/Charge 7-OHMTX 7-Hydroxymethotrexate 7-OHDAMPA 4-Amino 7-hydroxy-N^^-methylpteroic Acid Rs Resolution t % Half-life Vd Apparent Volume of Distribution TABLE OF CONTENTS PAGE LIST OF TABLES i LIST OF FIGURES V ACKNOWLEDGEMENTS xii DECLARATION xiii SUMMARY xiv CHAPTER 1 GENERAL INTRODUCTION GENERAL INTRODUCTION 1 Cell Kinetics 2 Behaviour of Cancer Cells 3 Drug Classification 4 The Effect of Anti-Cancer Drugs 4 CHAPTER 2 METHOTREXATE INTRODUCTION 9 HISTORY 9 STRUCTURE 9 MECHANISM OF ACTION 10 CLINICAL ASPECTS OF METHOTREXATE 11 Dosage 11 Toxicity 12 Avoidance of Methotrexate Toxicity 16 PHARMACOKINETICS 17 Absorption 17 Distribution 18 Metabolism 20 PAGE Excretion 22 METHOTREXATE ASSAYS 24 Biological Assays 24 Fluorimetric Methods 25 Dihydrofolic Acid Reductase 26 Inhibition Method Radioimmunoassay 26 Enzyme Immunoassay 27 Double-Antibody Enzyme Immunoassay 28 for Methotrexate High Performance Liquid Chromato- 29 graphy AIMS 31 CHAPTER 3 DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD FOR THE ESTIMATION OF METHOTREXATE AND ITS METABOLITES INTRODUCTION 33 lon-Pair Chromatography 34 MATERIALS AND EQUIPMENTS 35 Materials 35 Choice of L-Tryptophyl L-Glutamic 36 Acid as Internal Standard Apparatus 37 METHODS 38 Initial Chromatography 38 Sample Preparation 39 Quantitation 44 Linearity and Sensitivity 45 Recovery 45 PAGE Precision 46 Accuracy and Specificity 46 RESULTS 48 Initial Chromatography Method 48 Optimised Liquid Chromatography 49 Method Sample Preparation 49 Optimised Extraction Procedure 53 Linearity and Sensitivity 54 Recovery 54 Precision 54 Accuracy and Specificity 54 DISCUSSION 56 CHAPTER 4 IN VITRO SYNTHESIS OF METHOTREXATE METABOLITES INTRODUCTION 61 AIM 62 MATERIALS AND EQUIPMENTS 63 Materials 63 Apparatus 63 METHODS 63 Crude Enzyme Preparation 63 Semi-purified Enzyme Fractions 64 7-OHMTX Synthesis and Purification 65 Synthesis and Purification of 66 7-OHDAMPA Mass spectral and NMR analyses 66 PAGE RESULTS 67 Crude Enzyme Preparation 67 Semi-purified Enzyme Fractions 67 Synthesis of 7-OHMTX and 7-OHDAMPA 67 Identification of Synthesised 68 Products DISCUSSION 71 CHAPTER 5 CLINICAL STUDIES OF HIGH AND LOW- DOSE METHOTREXATE INTRODUCTION 73 Low-Dose 73 High-Dose 74 AIM 74 MATERIALS AND METHODS 75 Low-Dose Study 75 High-Dose Study 75 Analysis 75 Metabolite Identification 76 Pharmacokinetic Calculations 76 RESULTS 79 Low-Dose Studies 79 High-Dose Study 80 DISCUSSION 84 CHAPTER 6 IN VITRO STUDIES OF THE INTERACTIONS BETWEEN METHOTREXATE AND BACTERIAL AND HUMAN CULTURED CELLS INTRODUCTION 91 Bacteria 91 PAGE Human Culture Cell Lines 91 MATERIALS AND METHODS 92 Bacteria 92 Cells 94 RESULTS 96 Bacteria 96 Cells 96 DISCUSSION 99 CHAPTER 7 DEVELOPMENT AND APPLICATIONS OF AN ASSAY FOR THE DETERMINATION OF ANTHRACYCLINES IN BIOLOGICAL FLUIDS INTRODUCTION 102 Structure 102 Mechanism of Action and Usage 102 Dosage 103 Toxic Effects and Side Effects 103 Metabolism of Doxorubicin 105 Methods of Assay 106 Aims 109 MATERIALS AND METHODS 110 Apparatus 110 Extraction Procedure Development 111 Initial Development of Liquid 113 Chromatography Method Further Development ofthe HPLC 113 Method Linearity 115 Recovery 115 PAGE Precision 115 Accuracy 115 Sensitivity 116 Application of the Method to 116 Biological Specimens Method of Analysis 117 RESULTS 118 Extraction Procedure Development 118 Development of Liquid chromato­ 118 graphy Method Further Development of the HPLC 119 Method Linearity 120 Recovery 120 Precision 121 Accuracy 121 Sensitivity 121 Application of the Method to 121 Biological Specimens DISCUSSION 123 Method Development 123 Human Biological Fluids 126 Bacterial broth 127 CHAPTER 8 GENERAL DISCUSSION GENERAL DISCUSSION 129 Methotrexate 129 Anthracyclines 132 REFERENCES 134 LIST OF TABLES Following Table Page_____ 1 Marrow toxicity of some anti-cancer 5 drugs. 2 Toxic levels of MTX the toxicity risk 12 after 24, 48, 72 hours. 3 Aqueous solubility of MTX and 23 metabolites. 4 The characteristics of published HPLC 34 methods for MTX and its metabolites. 5 Comparison of k ' , Rs and Efficiency 48 obtained with solvents contain­ ing different proportions of MEOH: H3PO4. 6 Comparison between solvents with and 48 without ion-pair agents. 7 Absolute recoveries of MTX and DAMPA 49 following extraction from aqueous solutions by different organic solvents (n = 4 ). 8 Absolute recoveries of MTX and DAMPA 49 following extraction by different volumes of ethyl acetate: 2-propanol, 11 Following Table page_____ 9 The effect on the recovery of MTX 50 of dilution of serum before heat precipitation. 10 The effect of pH on the extraction of 50 MTX from a protein free supernatant by ethyl acetate ; isopropanol. I 11 Recovery of MTX and metabolites from 51 Dowex 1-X2 column before and after heat precipitation. 12 Effect of acetic acid on the elution 52 by methanol of MTX and DAMPA from Dowex 1-X2, 13 Internal standard concentrations 53 and detector attenuation used at different MTX concentrations. 14 Absolute recovery of MTX, 7-OHMTX and 54 DAMPA from serum (n = 16). 15 Precision studies on MTX in serum 54 (n - 16) and MTX and metabolites in urine {n = 36). 16 High resolution mass spectral data of 69 DAMPA and its metabolite. 17 The details of doses, courses for 75 patients treated with high-dose MTX therapy. IXX Following Table Page_____ 18 The bio avail ability of MTX for 14 79 patients treated with low doses (15 mg) orally and intravenously. 19 Individual pharmacokinetic parameters 79 for MTX following IV and oral MTX therapy in Psoriasis (15 rag). 20 Pharmacokinetics of high-dose metho- 82 trexate (MTX). 21 Human melanoma and choriocarcinoma 94 cells studied. 22 Summary of HPLC analyses of MTX and 97 7-OHMTX metabolism in vitro by different cell lines. 23 The characteristics of published HPLC 109 methods for ADR. 24 The capacity ratio ( k ' ) , reduced 119 plate height (h) and the resolution (Rs) for ADR and metabolites. 25 Effect of sulphonic acid chain length 119 and concentration on the k ’ of ADRone, ADRol, ADR and DAQN. 26 Absolute recovery of ADR and ADRol 120 using acetonitrile: methanol : water containing 1 mM octanesulphonic acid in proportions 30:40:30. iv Following Table Page 27 Absolute recovery of ADR and its 120 metabolite, using acetonitrile; 0.01M phosphoric acid containing 3 mM pentanesulphonic acid in proportions 35:65 as a mobile-phase. 28 Absolute recovery of ADR and its 120 metabolites using acetonitrile: 0.01 phosphoric acid containing 6 mM polyoxyethylene lauryl ether (Brij) in proportions 35:65 as a mobile- phase. 29 Precision studies on ADR, ADRol and 121 ADRone using different methods. 30 The percentage of unidentified peaks 122 present in cultures of different strains of gastrointestinal bacteria isolated from different patients. LIST OF FIGURES Following Figure page 1 Mechanism of action of methotrexate 9 and leucovorin-rescue. 2 Thestructure of methotrexate and its 9 analogues. 3 The metabolic pathway of methotrexate 20 4 The oxidation of MTX to yield a 25 fluorescent product. 5 The mode of action of a homogenous 27 enzyme immunoassay for a drug. 6 Chromatogram of MTX and metabolite 49 standards with L-tryptophyl L-glutamic acid as internal standard. 7 Association between serum MTX concen- 55 trations measured by EMIT and HPLC. 8 In vitro synthesis of 7-OHMTX from MTX 65 using rabbit liver homogenate. 9 The UV absorbance at 280 nm and enzyme 67 activity. 10 HPLC chromatograms obtained from 67 an extract of the crude enzyme preparation and MTX. vx Following Figure Page 11 HPLC of supernatants from the reaction 67 mixture of DAMPA incubated with crude enzyme preparation.
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