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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely afreet reproduction. 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 copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 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. UMI A Bell & Howell Information Company 300 North Zeeb Road, Aim Arbor MI 48106-1346 USA 313/761-4700 800/521-0600 DISPOSITION OF PROFLAVINE AND ACRIFLAVINE IN RAINBOW TROUT DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Zhengrong Yu, B.S., M.S. The Ohio State University 1996 Dissertation Committee: Dr. William L. Hayton, Adviser Approved by Dr. Kenneth K. Chan Dr. William J. Collins Adviser' Dr. Richard H. Reuning College of Pharmacy UMI Number: 9710692 UMI Microform 9710692 Copyright 1997, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeh Road Ann Arbor, MI 48103 DISPOSITION OF PROFLAVINE AND ACRIFLAVINE IN RAINBOW TROUT By Zhengrong Yu, Ph.D. The Ohio State University, 1996 Professor William L. Hayton, Adviser Acriflavine (3,6-diamino-10-methyl acridine. A) and proflavine (3,6- diamlnoacridine, P) have potential for use in aquaculture as antiinfectives; knowledge of their disposition in fish would guide their effective use while avoiding human exposure. This dissertation describes: (1) an HPLC method for A, P and their metabolites, (2) the pharmacokinetics of A and P in trout, (3) disposition of A and P in trout after water exposure, and (4) the metabolite profile of P in trout. The HPLC method for the determination of A, P, and their metabolites in fish fluids and tissues involved solid-phase extraction for sample clean-up, and gradient, reversed-phase HPLC separation with UV detection. The pharmacokinetic behaviors of A and P were comparable; their plasma concentration-time profiles appeared triexponential after intravascular bolus administration, and the terminal half-lives were 25.9 hr for P and 38.3 hr for A. Large Vgg values indicated that they distributed extensively into tissues, possibly due to avid binding to DNA. Since A and P ionize at pH 7-8, their branchial elimination was low and their elimination was via metabolic and renal pathways. Disposition of A and P was studied at various times after water exposure of the fish for 4 hr to 4 ppm ’^C-proflavine or ^^C-acriflavine. Immediately after exposure, the concentration of radioactivity in all tissues and fluids was below the exposure water concentration, except for bile. The rank order of residue concentration (high to low) was bile > kidney > liver > skin > plasma > muscle. During the 8 day depuration period, the rank order of residue concentration in the tissues was the same as at the end of exposure. The relatively high concentrations of acriflavine in skin and kidney after 16 days of depuration were probably due to irreversible binding. Metabolites observed from P-treated fish were characterized by acid hydrolysis, enzymatic treatment, UV-VIS absorption and mass spectra. The metabolites were determined to be 3-N-glucuronosyl proflavine (PG), 3-N- glucuronosyl, 6-N-acetyl proflavine (APG), and 3-N-acetyl proflavine (AP). Metabolite identities were verified by chemical synthesis and HPLC co-elution. An in vitro study confirmed this characterization and showed that APG can form from glucuronidation of AP or acétylation of PG. Finally, a mass balance study showed a 90% recovery of the administered dose, and supported the conclusion that other metabolic pathways were not significant. iii To my family IV ACKNOWLEDGMENTS I would like to express my most sincere gratitude to my advisor, Dr. William L. Hayton, for his invaluable instruction, encouragement and personal concern throughout this study. With much sincerity, I wish to express my personal appreciation to Dr. Kenneth K Chan for his help and advice on the metabolites analysis. Appreciation goes to the other members of my advisory committee, Drs. William J. Collins and Richard H. Reuning, for their comments, suggestions, and help. The technical assistance of Mr. Andy Vick, Brian Kemmenoe and Tim He is gratefully acknowledged. Further, I am thankful to Dr. Annamaria Szoke for her friendship and stimulating discussions. Thanks go to my fellow graduate students, Kelli Clark, Erin Swope, Kirsten Engelfried, Hong Mei and the graduate students in the College of Pharmacy for their encouragement and friendship. Finally, financial assistance from The Ohio State University, College of Pharmacy, and the U.S. Food and Drug Administration Center for Veterinary Medicine is gratefully acknowledged. VITA October 13,1968 ................................................. Bom - Qiqihar, China 1991..................................................................... 8.S. in Pharmacy Beijing Medical University Beijing, China 1993..................................................................... M.S. in Chemistry Cleveland State University Cleveland, Ohio 1991 -1993......................................................... Teaching Associate, Department of Chemistry, Cleveland State University 1993 -1996......................................................... Teaching Associate, Graduate Research Associate, College of Pharmacy, The Ohio State University PUBLICATIONS AND PRESENTATIONS (1) "Pharmacokinetics of Cortisol in Rabbits", Z. Yu, B. S. Thesis, Beijing Medical University, Beijing, China, 1991. (2) "An Ultra-sensitive Electrochemical Enzyme Immunoassay for Thyroid Stimulating Hormone in Human Serum", Z Yu, Y. Xu, and M. P. C. Ip, J. Pharm. and Biomed. Analysis 1994. 12: 787-93. (3) "Adsorption Profiles of Active Antibodies on Negatively Charged Polystyrene Microtiter Plates", Y. Xu, Z. Yu, W. R. Heinemann and H. B. Halsall, Anal. Biochem., submitted. vi (4) "Heterogeneous Enzyme Immunoassay for Thyroid Stimulating Hormone in Human Serum by Flow Injection Amperometric Detection", Z. Yu, Y. Xu, and M. P. C. Ip, Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, Atlanta, Georgia, March 8-12,1993 (5) "Separation of Proflavine and Acriflavine by Reverse Phase HPLC", Z Yu, A. Szoke, and W. L. Hayton, Annual meeting of Society of Environmental Toxicology and Chemistry, Denver, Colorado, October 30 - November 4,1994. (6) "Pharmacokinetics of Proflavine in Rainbow Trout", Z Yu, R. Abbas, A. Vick, S. Doddapneni, and W. L Hayton, Annual meeting of Society of Toxicology and Chemistry, Denver, Colorado, October 30 - November 4,1994. (7) "Separation of Proflavine and Acriflavine by Reverse Phase HPLC", Z Yu, A. Szoke, and W. L. Hayton, Annual meeting of American Association of Pharmaceutical Scientists, San Diego, California, November 6-10,1994. (8) "Pharmacokinetics of Proflavine in Rainbow Trout", Z Yu, R. Abbas, A. Vick, S. Doddapaneni, and W. L. Hayton, Annual meeting of American Association of Pharmaceutical Scientists, San Diego, California, November 6-10, 1994. (9) "Pharmacokinetics of Acriflavine in Rainbow Trout", W. L. Hayton, Z. Yu, and A. Vick, International Congress of Toxicology VII, Seattle, Washington, July 2-6, 1995. (10) "Electrochemical Enzyme Immunoassay for Thyroid Stimulating Hormone in Human Serum", Y. Xu, Z. Yu, and M. P. C. Ip., the 22nd Annual Conference of the Federation of Analytical Chemistry and Spectroscopy Societies, Cincinnati, Ohio, October 15-20, 1995. (11) "Pharmacokinetics of Acriflavine and Its Metabolite in Rainbow Trout", Z. Yu, A. Vick, and W. L. Hayton, Annual meeting of American Association of Pharmaceutical Scientists, Miami, Florida, November 5-9, 1995. (12) "Metabolic Fate of Proflavine and Acriflavine in Rainbow Trout", Z Yu, W. L. Hayton and K. K. Chan, Annual meeting of Society of Toxicology, Anaheim, California, March 10-14, 1996. (13) "Characterization of Proflavine Metabolites in Rainbow Trout", Z. Yu, W. L. Hayton and K K. Chan, Annual meeting of American Association of Pharmaceutical Scientists, Seattle, Washington, October 26-31,1996. VII FIELDS OF STUDY Major Field; Pharmacy Studies in Analytical Method Development, Pharmacokinetics and Disposition, Drug Metabolism VIII TABLE OF CONTENTS Dedication ........................................................................................................................ iv Acknowledgments ............................................................................................................v
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