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University Microfilms International 300 N. Zeeb Road Ann Arbor, Ml 48106 8400151 Alexander, Michael Stephen METABOLISM AND DISPOSITION OF ACEBUTOLOL The Ohio State University Ph.D. 1983 University Microfilms International300 N. Zeeb Road, Ann Arbor, Ml 48106 Copyright 1984 by Alexander, Michael Stephen All Rights Reserved METABOLISM AND DISPOSITION OP ACEBUTOLOL DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Michael S. Alexander, B.S., M.S. ********** The Ohio State University 1983 Reading Committee: Approved By Brian D. Andresen, Ph. D. Sarah Tjioe, Ph. D. Howard Sprecher, Ph. D. Brian D. Andresen, PhD. Department of Pharmacology METABOLISM AND DISPOSITION OP ACEBUTOLOL By Michael S. Alexander, Ph. D. The Ohio State University Professor Brian D. Andresen, Advisor Acebutolol disposition and metabolism have been studied in both rats and humans. Animal studies indicate acebutolol is metabolized in a two step process, with debutyration the rate-limiting step in the rat. Processes first examined in isolated, perfused rat livers were found to be reliable predictors of in vivo events. Specifically radiolabelled acebutolol was synthesized by an improved procedure and used as a probe to show the presence of several new metabol ites in the animal. In a large human study, the kinetics of acebutolol and both its known metabolites were simultaneous ly quantitated for the first time. It was shown that elimin ation of acebutolol following intravenous administration is triphasic, most probably reflecting filling and equilibra- ii tion of the enterohepatic subcompartment. About half the subjects showed elevated levels of acetolol, the metabolic intermediate in conversion of acebutolol to diacetolol, in their plasma following a 400 mg oral dose of acebutolol. This suggests that a significant portion of the population will experience elevated levels of a circulating aniline derivative after taking oral acebutolol. ACKNOWLEDGEMENTS Dr. Joseph Bianchine, for his acceptance and continuing personal and financial support. Dr. Brian Andresen, for proposing this project, securing its funding, and giving both advice and the freedom of inquiry. Dr. Matana Borrisud, for her material help and friendship. Robert Kreitman, for living proof that unrestrained enthusiasm for science still exists. The Central Ohio Heart Association for two years of needed grant support in my acebutolol study. Dr. Sheila Auster, for reasons too long to list. Okay, I'll try: love, patience, laughter, patience, support, patience, neat car, patience... iii VITA September 29> 1950......... Born - Cleveland, Ohio 1972......................... B.S., University of Notre Dame, Notre Dame, Indiana 1972-1978.................... Research Assistant, Dept of Chemistry, The Ohio State University, Columbus, Ohio 1978......................... M.S., The Ohio State University, Columbus, Ohio 1978-1980.................... Research Assistant, Dept, of Pharmacology, The Ohio State University, Columbus, Ohio I98O-I983............... Research Associate, Dept, of Pharmacology, The Ohio State University, Columbus, Ohio AWARDS National Merit Scholarship, University of Notre Dame (1968 - 1972) Winner, ICSABER Biomedical Research Competition, College of Medicine, The Ohio State University (1982) PUBLICATIONS Argentation thin-layer chromatography of arachidonic acid metabolites isolated from human platelets, J. Greenwald, M. Alexander, M. VanRollins, L. Wong and J. Bianchine, Prostaglandins, 21(1), 33 (1981). iv Complete separation by high performance liquid chromatog raphy of metabolites of arachidonic acid from incubation with human and rabbit platelets, M. VanRollins, S. Ho, J. Greenwald, M. Alexander, N. Dorman, L. Wong, L. Horrocks, Prostaglandins, 2_0(3), 571 (1980). Role of ferric iron in platelet lipoxygenase activity, J. Greenwald, M. Alexander, R. Fertel, C. Beach, L. Wong, J. Bianchine, Biochem. Biophys. Res. Comm., 96(2), 817 (1980). "Prostaglandin alterations in pregnancy", J. Dicke, J. Greenwald, M. Alexander, J. Bianchine, F. Zuspan. In Pregnancy Hypertension, Sammour, Symonds, Zuspan and El-Tomi (eds.), Aim Shams University Press, Cairo, Egypt (1982). ABSTRACTS "HETE production in pregnancy", J. Dicke, J. Greenwald, M. Alexander, F. Zuspan, J. Bianchine, L. Wong, Society for Gynecologic Investigation, Denver, Colorado, 1980. "Acebutolol metabolism in the isolated, perfused rat liver", M. Alexander and B. Andresen, American Society for Clinical Pharmacology and Theraputics, Lake Buena Vista, Florida, 1982. "Salicylate determination in Reye’s syndrome by HPLC", M. Alexander, B. Andresen, J. Bianchine, American Society for Pharmacology and Experimental Theraputics/Society of Toxicology Joint Meeting, Louisville, Kentucky, 1982. FIELDS OF STUDY Major Fields: Pharmacology and Chemistry Studies in Natural Product Synthesis and Characterization (Derek Horton, Ph.D.) Studies in Prostaglandin Metabolism (Joseph Bianchine, M.D., Ph.D.) Studies in Salicylate Kinetics (Brian Andresen, Ph.D.) Studies in Acebutolol Dynamics (Brian Andresen, Ph.D.) v TABLE OF CONTENTS Page DEDICATION................................................. ii ACKNOWLEDGEMENTS ..................................... iii VITA......................... iv LIST OF TABLES............................................. vii LIST OF FIGURES............................................ iX CHAPTER I Introduction............................................ 1 Statement of the Problem.............................. 16 CHAPTER II Experimental Chemical Syntheses................................. 19 Isolated Liver Perfusion...... 31 In Vivo Animal Studies............................. 35 Human Studies....................................... 35 CHAPTER III Results and Discussion Syntheses............................................ 55 Animal Experiments................................. 62 Human Studies............................... 98 CHAPTER IV Summary................................................. 129 BIBLIOGRAPHY............................................... 131 LIST OP TABLES Table Page 1 Schedule for Collection of Blood Specimens Following AOOmg Acebutolol Oral Dose....... 37 2 Schedule for Collection of Blood Specimens Following lOOmg Acebutolol Intravenous Dose.......... 38 3 Standard Statistical Table for Subject Weight Inclusion Criterion.................. 39 A Subject Dose Randomization Code............. A3 5 Laboratory Evaluation Tests.................. A6 6 Acebutolol Half-Lives for Patient # 1...... 53 7 Values for AUC, Clearance and Clearance/ Kilogram for Subjects Recieving AOOmg Acebutolol Oral Dose......................... 106 8 Values for AUC, Clearance and Clearance/ , Kilogram for Subjects Recieving lOOmg Acebutolol Intravenous Dose...... 107 9 Terminal Half-Life, Time to Maximum Concentration and Maximum Plasma Concentration for Acebutolol in Subjects Recieving AOOmg Acebutolol Oral Dose....... 109 10 Terminal Half-Life, Time to Maximum Concentration and Maximum Plasma Concentration for Diacetolol in Subjects Recieving AOOmg Acebutolol Oral Dose....... 110 11 Terminal Half-life, Time to Maximum Concentration and Maximum Plasma Concentration for Acetolol in Subjects Recieving AOOmg Acebutolol Oral Dose....... Ill 12 Terminal Half-Life, Time to Maximum Concentration and Maximum Plasma vii Concentration for Acebutolol in Subjects Recieving lOOmg Acebutolol Intravenous Dose......................................... 1 1 2 13 Half-Life Values for Plasma Concentration of Acebutolol In Subjects