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INFORMATION TO USERS The most advanced technology has been used to photo graph and reproduce this manuscript from the microfilm master. UMI films the original text directly from the copy submitted. Thus, some dissertation copies are in typewriter face, while others may be from a computer printer. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyrighted material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are re produced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each oversize page is available as one exposure on a standard 35 mm slide or as a 17" x 23" black and white photographic print for an additional charge. Photographs included in the original manuscript have been reproduced xerographically in this copy. 35 mm slides or 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. up Accessing theUMI World's Information since 1938 300 North Zeeb Road, Ann Arbor Ml 48106-1346 USA Order Number 8824619 Studies on the metabolism of merbarone in man Supko, Jeffrey G., Ph.D. The Ohio State University, 1988 UMI 300 N. Zeeb Rd. Ann Arbor, MI 48'06 PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark V . 1. Glossy photographs or pages______ 2. Colored illustrations, paper or print_______ 3. Photographs with dark background_____ 4. Illustrations are poor copy_______ 5. Pages with black marks, not original copy ^ 6. Print shows through as there is text on both sides of page_______ 7. Indistinct, broken or small print on several pages 8. Print exceeds margin requirements______ 9. Tightly bound copy with print lost in spine_______ 10. Computer printout pages with indistinct print_______ 11. Page(s)____________lacking when material received, and not available from school or author. 12. Page(s) seem to be missing in numbering only as text follows. 13. Two pages num bered . Text follows. 14. Curling and wrinkled pages 'S 15. Dissertation contains pages with print at a slant, filmed as received 16. Other Studios on the, Metabolism of Merbarono in Han DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jeffrey G. Supko, B.S. •jV Vr Vr «sV Vr The Ohio State University 1988 Dissertation Committee: Approved by Louis Malspeis, Ph.D. Alfred E. Staubus, Ph.D Robert E. Notari, Ph.D. Louis Malspeis, Advi Division of Pharmaceutics and Pharmaceutical Chemistry College of Pharmacy DF.DTCATION To my wife and parents. ii ACKNOWLEDGEMENTS I wish to express my most sincere appreciation to Dr. Louis Malspeis for his invaluable guidance throughout the course of my graduate studies. He is truly a preeminent scientist and has been a great inspiration to continually enhance my knowledge and research proficiency. Gratitude is also expressed to Drs. Robert E. Notari and Alfred E. Staubus who have significantly contributed to my development as a graduate student. Furthermore, it has not been forgotten that through his earnest recruiting efforts, Dr. Notari first intoduced me to both the discipline of Pharmaceutical Chemistry and my wife, for which I am most appreciative. The technical assistance of Mr. Michael T. Fox and Ms. Margaret E. Lyon is gratefully acknowledged. VITA September 23, 1960 Born - Hackensack, New Jersey December, 1983 B.S. cum laude - Double Major Chemistry and Chemistry/Business University of Scranton Sept. 1983 - Aug. 1987 Graduate Teaching Assistant Sept. 1987 - present Berlex Fellow College of Pharmacy The Ohio State University Columbus, Ohio Publications "Pharmacokinetics and Metabolism of Merbarone (NSC 336628) in Patients." L. Malspeis, A. E. Staubus, J. G. Supko, M. R. Grever and E. H. Kraut. Proc. Am. Assoc. Cancer Res., 28, 228 (1987). "Spectral Characterization and Quantitation of the Principal Metabolites of Merbarone (NSC 336628) in the Urine of Patients." J. G. Supko, M. R. Grever, S. P. Balcerzak, E. H. Kraut, A. E. Staubus and L. Malspeis. Proc. Am. Assoc. Cancer Res., 29, 189 (1988). "Merbarone (NSC 336628) Enhances the Urinary Excretion of Uric Acid of Cancer Patients." M. R. Grever, E. H. Kraut, J. G. Supko, R. W. Trewyn, A. E. Staubus and L. Malspeis. Proc. Am. Assoc. Cancer Res., 29, 189, (1988). Field of Study Major Field Pharmaceutics and Pharmaceutical Chemistry iv TABLE OF CONTENTS PAGE DEDICATION ............................................................... ii ACKNOWLEDGEMENTS ........................................................ iii VITA ...................................................................... iv LIST OF TABLES ........................................................ viii LIST OF FIGURES ......................................................... xi INTRODUCTION ............................................................. 1 CHAPTER I. CHARACTERIZATION OF MERBARONE METABOLITES IN MAN .......... 3 A. Introduction ............................................... 3 B. Materials and Methods..................................... 6 1. Patient Urine and Plasma Samples .................... 6 2. Chemicals and Materials .............................. 6 3. Reagent and Solvent Purification ................... 8 4. Instrumentation ....................................... 9 5. High Performance Liquid Chromatography .......... 10 a. Apparatus ........................................ 10 b. Sample Preparation .............................. 10 c. Chromatographic Conditions ..................... 10 6 . Chemical Syntheses ................................... 10 7. Extraction of Metabolites from Patient Urine ...... 15 8 . Acetylation of Phenolic Metabolites Isolated from Urine ................................................. 16 C. Results and Discussion ................................... 17 1. The Metabolism of Functionally Related Xenobiotics 17 2. Synthesis of Potential Oxidative Metabolites ...... 19 3. Metabolite Characterization ......................... 22 v 2. Synthesis of Potential Oxidative Metabolites ........ 19 3. Metabolite Characterization ......................... 22 D. References ................................................. 33 II. ANALYSIS OF MERBARONE AND TTS METABOLITES IN HUMAN URINE BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY ........... 110 A. Introduction .............................................. 110 B. Materials and Methods ..................................... Ill 1. Reagents and Chemicals ............................... Ill 2. Apparatus .............................................. 112 3. Standard Solutions ................................... 113 4. Optimization of Reaction Conditions ................ 114 5. Sample Preparation ................................... 115 6 . Chomatographic Conditions ........................... 116 7. Quantitation .......................................... 116 8 . Relative Recovery .................................... 116 9. Stability of the Acetate Derivatives ............... 116 C. Results and Discussion ................................... 117 D. References ................................................. 128 III. EXCRETION OF MERBARONE AND ITS MAJOR METABOLITES IN HUMAN URINE .................................................... 166 A. Introduction ............................................... 166 B. Materials and Methods .................................... 169 1. Acquisition of Human Urine and Plasma Specimens ... 169 2. Analytical Method .................................... 169 3. Plasma Sample Preparation ........................... 169 C. Results and Discussion ................................... 170 D. References ................................................. 175 IV. XANTHINE OXIDASE INHIBITION STUDIES ......................... 190 A. Introduction ............................................... 190 B. Materials and Methods .................................... 191 1. Reagents and Chemicals ............................... 191 2. Apparatus ............................................. 192 3. Stock Solutions ....................................... 192 4. Standard Solutions ................................... 193 5. Spectrophotometer Parameters ........................ 194 vi C. Results and Discussion .................................. 196 D. References ................................................ 203 BIBLIOGRAPHY ............................................................. 212 vii I.TST OF TABLES Reaction yields and appearance of the synthesized 5-carboxanilide barbiturates |1| and |3|............................. 37 HPLC retention and UV spectral data of the 5-carboxanilide barbiturates I and 3. Tsocratic, C^g reverse-phase chroma tography was performed at ambient temperature employing a mobile phase of 25% methanol (v/v), 0.1 M acetate buffer, 40 mM magnesium sulfate and 1 mM SOS at pH 5.5; flow rate 1.0 mL/min...................................................... 38 ^11 NMR spectral data of the 5-cnrboxani.li.de barbiturates _1 and 3 ............................................................ 39 1 3 C NMR chemical shifts (6 ) for the 5-carboxanilide barbiturates J. and 3 ........................................... 40 Electron

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