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THE POSSIBLE ROLE of LEUKOCYTE-GENERATED Reactrve INTERMEDIATES in the DRUG-INDUCED Agrancnocytosis

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THE POSSIBLE ROLE of LEUKOCYTE-GENERATED Reactrve INTERMEDIATES in the DRUG-INDUCED Agrancnocytosis THE POSSIBLE ROLE OF LEUKOCYTE-GENERATED REACTrVE INTERMEDIATES IN THE DRUG-INDUCED AGRANCnOCYTOSIS Zhao Chao Liu A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Faculty of Pharmacy University of Toronto O Copyright by Zhao Chao Liu 1997 National Library Bibliothèque nationale (*m of Canada du Canada Acquisitions and Acquisitions et Bibliographic Services services bibliographiques 395 Wellington Street 395, rue Wellington Ottawa ON K1A ON4 Ottawa ON KIA ON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant a la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seil reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la fome de microfiche/£ïlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. ABSTRACT Ticlopidine and clczapine are associated with relatively high incidences of agranulocytosis. 5-aminosalicylic acid (5-ASA) is an agent widely used in the treatment of inflammatory bowel disease. It has been demonstrated that many drugs associated with drug-induced agranulocytosis or dmg-induced lupus are oxidized by activated neutrophils to reactive intermediates, by the combination of myeloperoxidase (MPO), hydrogen peroxide and chloride ion, or simply by hypochlorous acid (HOCI). We set out to test the hypothesis that ticlopidine, clozapine and 5-ASA fit this pattern and are oxidized to reactive intermediates by activated neutrophils and HOCI. The mass spectra of the reactive intermediates of ticlopidine, clozapine and 5- ASA were obtained by using a flow system coupled with a Sciex MI III mass spectrometer. We have shown that as much as 8% ticlopidine was metabolized by activated human neutrophils to a dehydro-ticlopidine. A neutrophil-derived reactive intermediate of ticlopidine was trapped with glutathione (GSH) and the same ticlopidine-GSH conjugate was found in both the MPO and HOCl systems. The reactive intermediate was putatively a thiophene-S-diloride. Clozapine was oxidized by HOCl to a reactive intermediate that was hypothesized to be a forma1 nitrenium ion in which the positive charge is highly delocalized. Clozapine was also oxidized by activated neutrophils and the GSH conjugates were formed. When therapeutic concentrations of radiolabeled clozapine were used, up to 7% of the dmg became irreversibly bound to the neutrophils. These two reactive intermediates may be responsible for drug-induced agranulocytosis. c We studied the oxidation of 5-ASA by HOC1 and characterized the reaction pathway involving iminoquinone and quinone as reactive intermediates. The major stable product formed was identified as gentisic acid. The iminoquinone and quinone intermediates were trapped by GSH and the products analyzed by liquid chromatography-mass spectrometry (LC/MÇ). Covalent binding of the reactive intemediates to the alpha chah of human hemoglobin was also observed. The iminoquinone is proposed to be the major intemediate and it may be responsible for the antiinflarnmatory effects of the dmg as well as the adverse dmg reactions which are associated with the use of 5-ASA. DEDICATIONS This thesis is dedicated to: MY PARENTS ACKNOWLEDGMENTS I sincerely thank my supervisor, Professor Jack Uetrecht, for his guidance and encouragement throughout my thesis project and for providing me with the opportunities to present my research at scientific meetings. 1am grateful to Dr. Robert A. McClelland for his guidance in the mechanistic studies and genuine technical support in conducting various experirnental procedures of this project. 1 am grateful to Dr. Henrianna Pang for her suggestions and help in conducting the mass spectral analysis. I am grateful to Mr. Nasir Zahid for his patience and techicai support. 1 wish to thank Drs. Alexander G. Harrison and Peter G. Wells for their vaiuable suggestions and critical review of the thesis hrpotheses and objectives. 1 thank Drs. Deborah Nicoll-Griffith and Peter O'Brien for spending sa much time on critical reviewing my thesis as extemal examiner and interna1 appraiser. 1 would like to thank the following colleagues for their various scientific and moral support during the completion of this thesis: Miyamoto, Ian, Bridget, Sylvia, Henry, Ebrahim, Kenny ,Taras, Christian and Christ. 1 am thankful to Dr. Dennis Whitefield for NMR analysis of clozapine samples. c ACKNOWLEDGMENT OF FINANCIAL ASSISTANCE The investigations described in this thesis were fmancially supported by research grants fiom the Medical Research Council of Canada and Sandoz Canada. The mass spectrd facilities were supported by MDS Inc., Toronto, Canada and the Medical Research Council of Canada. The investigations were carried out in Professor Jack P. Uetrecht's laboratory in the Faculty of Pharmacy, at the University of Toronto, 19 Russell Street, Toronto, Ontario, Canada. Zhao Chao Liu was financially supported by an University of Toronto Open c Fellowship (1 992- 1996). TABLE OF CONTENTS Topic Page Title Abstract Dedications Acknowledgments Acknowledgment of Financial Support Table of Contents Summary of Thesis Publications Surnrnary of Abbreviations Summary of Tables Summary of Figures Chapter 1 General Introduction 1.1 Statement of problem rationale and research objectives 1.2 Overall Hypotheses 1.3 Adverse drug reactions 1.3.1 Adverse drug reactions 1.3.2 Clinical manifestations of adverse drug reactions 1.3.3 Possible mechanisms of idiosyncratic reactions 1.4 Metabolism of dmgs by activated neutrophils 1.4.1 Metabolism of dmgs by activated neutrophils 1.4.2 Metabolism of drugs involved in hg-induced agranulocytosis 1.S. General metabolkm of ticlopidine, clozapine and 5-ASA 1S. 1 Metabolism of ticlopidine 1.5.2 Metabolism of clozapine 1S.3 Metabolism of 5-ASA Chapter 2 Materials and Methods 2.1 Chernicals 2.2 Analfical 2.3 Neutrophil isolation Chapter 3 Metabolism Of Ticlopidine By Activated Neutrophils: Implications For Ticlopidine-Induced Agranulocytosis 3.1 Abstract 3.2 Introduction 3.3 Methods 3.3.1 Analytical 3.3.2 Metabolism of ticlopidine by activated neutrophils 3.3.3 Metabolism of ticlopidine by the MPO system 3.3.4 Oxidation of ticlopidine by hypochlorous acid v iii 3.4 Results 3.4.1 Metabolism of ticlopidine by activated neutrophils 3.4.2 Metabolism of ticlopidine by the MPO system 3.4.3 Oxidation of ticlopidine by hypochlorous acid 3.5 Discussion Chapter 4 Clozapine is Oxidized by Activated Human Neutrophils to a Reactive Niû-enium Ion that heversibly Binds to the Cells 4.1 Abstract 4.2 Introduction 4.3 Methods 4.3.1 Analytical 4.3.2 Oxidation of clozapine by hypochlorous acid c 4.3.3 Synthesis of GSH adducts of the reactive intermediate 4.3.4 Metabolism of clozapine by activated neutrophils in the presence of GSH 4.3 -5 Covalent binding of clozapine to neutrophils 4.3.6 Metabolism of clozapine by the MPO system 4.4. Results 4.4.1 Oxidation of clozapine by hypochlorous acid 4.4.2 Clozapine-GSH adducts 4.4.3 Metabolism of clozapine by activated neutrophils in the presence of GSH 4.4.4 Covalent binding of clozapine to neutrophils 4.4.5 Metabolism of clozapine by the MPO system 4.5 Discussion c Chapter 5 Oxidation Of 5-Aminosalicylic Acid By Hypochlorous Acid 1 15 To A Reactive Irninoquinone: Possible Role In The Treatment Of Infiammatory Bowel Diseases 5.1 Abstract 5.2 Introduction 5.3 Methods 5.3.1 Reaction 5-ASA with HOC1 and analysis of the products by HPLC 5.3.2 Identification of reactive intermediates by mass spectrometry in a flow reactor 5.3.3 Trapping of intermediates with GSH and hemoglobin 5.3.4 Reaction kinetics as determined by spectrophotornetry 5.3.5 Metabolism of 5-ASA by the MPO system 5.3.6 Metabolism of 5-ASA by activated neutrophils 5.4 Results 5.4.1 Identification of the products of the reaction of 5-ASA with HOCl 5.4.2 Kinetics of the oxidation of 5-ASA by HOCl 5.4.3 GSH conjugates 5.4.4 Covalent binding of 5-ASA to hemoglobin and arnino acids 5.4.5 Oxidation of 5-ASA by the MPO system 5.4.6 Metabolism of 5-ASA by activated neutrophils 5.5 Discussion c Chapter 6 Summary, conclusion and discussion 6.1 Summaiy and conclusion 6.2 Discussion References SUMMARY OF THESIS PUBLICATIONS Zhao Chao Liu, Nasir Zahid and Jack Uetrecht: Metaboliçm of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. Chemical Research in Toxicology subrnitted, 1997 (Chapter 3 of the thesis) Zhao Chao Liu and Jack Uetrecht: Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to the cells. Jownal of Pharmacology & Experimental Therapeutics. 275: 1476-83, 1995. (Chapter 4 of the thesis) Zhao Chao Liu, Robert A, McCleIland and Jack Uetrecht: Oxidation of 5- aminosalicylic acid by hypochlorous acid to a reactive iminoquinone. Possible role in the treatment of inflammatory bowel diseases. Drug Metabolism and Disposition. 23: 246-50, 1995. (Chapter 5 of the thesis). xii Q SUMMARY OF ABBREVIATIONS 5-ASA 5-aminosaiicylic acid ADR adverse dmg reaction CID collisional-induced dissociation COSY
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