AN ABSTRACT OF THE THESIS OF WATTANAPORN TAVIPATANA for the degree of Master of Science in Pharmacy presented on April 30, 1984. Title: Pharmacokinetics of Theophylline and its N-7 Derivatives in Rabbits Redacted for Privacy Abstract approved: Dr. Jamey r. Ayres Pharmacokinetics of theophylline and N-7 substituted theophylline in rabbits when administered alone and in various combinations were investigated. This thesis has four chapters dealing with etophylline and theophylline; proxyphylline and theophylline; dyphylline and theophylline; and etophylline, proxyphylline and dyphylline phar- macokinetics when administered concomitantly. All chapters are interrelated. Each chapter has its own abstract. PHARMACOKINETICS OF THEOPHYLLINE AND IT'S N-7 DERIVATIVES IN RABBITS by Wattanaporn Tavipatana A THESIS Submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science Completed April 30, 1984 Commencement June 1984 APPROVED: Redacted for Privacy Proffeissor of Pharmdci /In Charge of Major Redacted for Privacy Deah of College of Pharmacy Redacted for Privacy Dean of bcnool Date thesis is presented April 30, 1984 Typed by Elaine Plaggert for Wattanaporn Tavipatana ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. J. W. Ayres for his friendliness, patience, encouragement and constant guidance throughout my research work. I wish to express my sincere appreciation to Dr. J. M. Christensen and Dr. D. Thomas for their suggestions and advice. I am deeply gratejul to my parents for their never ending love, encouragement and financial support. My special thanks to Mike Cole for his valuable assistance. TABLE OF CONTENTS CHAPTER I: ETOPHYLLINE AND THEOPHYLLINE 1 PHARMACOKINETICS WHEN ADMINISTERED CONCOMITANTLY ABSTRACT 2 INTRODUCTION 3 MATERIALS AND METHODS 6 RESULTS AND DISCUSSION 10 CONCLUSION 34 ENDNOTES 35 REFERENCES 37 CHAPTER II: PROXYPHYLLINE AND THEOPHYLLINE 40 PHARMACOKINETICS WHEN ADMINISTERED CONCOMITANTLY ABSTRACT 41 INTRODUCTION 43 MATERIALS AND METHODS 46 RESULTS AND DISCUSSION 48 CONCLUSION 69 ENDNOTES 70 REFERENCES 71 CHAPTER III: DYPHYLLINE AND THEOPHYLLINE 73 PHARMACOKINETICS WHEN ADMINISTERED CONCOMITANTLY ABSTRACT 74 INTRODUCTION 76 MATERIALS AND METHODS 79 RESULTS AND DISCUSSION 81 CONCLUSION 103 ENDNOTES 104 REFERENCES 105 CHAPTER IV: ETOPHYLLINE, PROXYPHYLLINE AND 108 DYPHYLLINE PHARMACOKINETICS WHEN ADMINISTERED CONCOMITANTLY ABSTRACT 109 INTRODUCTION 111 MATERIALS AND METHODS 114 RESULTS AND DISCUSSION 117 CONCLUSION 154 ENDNOTES 155 REFERENCES 156 BIBLIOGRAPHY 158 APPENDICES 161 LIST OF FIGURES Figure Page I.1 Plasma concentraton time curves for 11 theophyline after administration of aminophylline (40 mg/kg intravenous infusion over 30 minutes) in 6 rabbits. I. 2a Plasma concentration time curves for 12 theophylline after administration of aminophylline (40 mg/kg intravenous infusin over 30 minutes) followed by etophylline loading dose (150 mg/kg intravenous infusion over 5 minutes) and etophylline maintenance dose (30 mg/kg/hr intravenous infusion over 2 hours) in 6 rabbits. I.2b Plasma concentration time curves for 13 etophylline after administration of aminophylline (40 mg/kg intravenous infusin over 30 minutes) followed by etophylline loading dose (150 mg/kg intravenous infusion over 5 minutes) and etophylline maintenance dose (30 mg/kg/hr intravenous infusion over 2 hours) in 6 rabbits. I .3a Plasma concentration time curves for 14 etophylline after administration of etophylline (150 mg/kg intravenous infusin over 5 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in rabbits. I.3b Plasma concentration time curves for 15 theophylline after administration of etophylline (150 mg/kg intravenous infusion over 5 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in 6 rabbits. 1.4 Plasma concentration time curves for 16 theophylline fitted by a two compartment open model after administration of aminophylline (40 mg/kg intravenous infusin over 30 minutes) in Subject D. Figure Page 1.5 Plasma concentration time curves for 17 theophylline (*) and etophylline (*) after administration of aminophylline (40 mg/kg intravenous infusion over 30 minutes) followed by etophylline loading dose (150 mg/kg intravenous infusion over 5 minutes) and eto- phylline maintenance dose (30 mg/kg/hr intravenous infusion over 2 hours) in subject Q. 1.6 Plasma concentration time curves for 18 theophylline (m) fitted by a two com- partment open model and etophylline (*) fitted by a three compartment open model after administration of etophylline (150 mg/kg intravenous infusion over 5 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in subject T. 1.7 Plasma concentration time curves for 27 etophylline after administration of etophylline (150 mg/kg intravenous infusion over 5 minutes) in 6 rabbits. 1.8 Etophylline plasma concentration time 28 curve fitted by a two compartment open model after administration of eto- phylline (150 mg/kg intravenous infusion over 5 minutes) in subject S. 1.9 Etophylline plasma concentration time 29 curve fitted by a three compartment open model after administration of eto- phylline (150 mg/kg intravenous infusion over 5 minutes) in subject EE. II.la Plasma concentration time curves for 49 theophylline after adminstration of aminophylline (40 mg/kg intravenous infusion over 30 minutes) followed by proxyphylline loading dose (135 mg/kg intravenous infusion over 5 minutes) and proxyphylline maintenance dose (15 mg/kg/hr intravenous infusion over 2 hours) in 6 rabbits. Figure Page II.lb Plasma concentration time curves for 50 proxyphylline after adminstration of aminophylline (40 mg/kg intravenous infusion over 30 minutes) and proxy- phylline loading dose (135 mg/kg intravenous infusion over 5 minutes) and proxyphylline maintenance dose (15 mg/kg/hr intravenous infusion over 2 hours) in 6 rabbits. II.2a Plasma concentration time curves for 51 proxyphylline after adminstration of proxyphylline (135 mg/kg intravenous infusion over 5 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in 6 rabbits. II.2b Plasma concentration time curves for 52 theophylline after adminstration of proxyphylline (135 mg/kg intravenous infusion over 5 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in 6 rabbits. 11.3 Plasma concentration time curves for 53 theophylline (0) and proxyphylline (0) after administration of aminophylline (40 mg/kg intravenous infusion over 30 minutes) followed by proxyphylline loading dose (135 mg/kg intravenous infusion over 5 minutes) and proxy- phylline maintenance dose (15 mg/kg/hr over 2 hours) in subject BE. 11.4 Typical plasma concentration time 54 curves for theophylline (0) and proxyphylline (0) after administration of proxyphylline (135 mg/kg intravenous infusion over 5 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in subject HH. 11.5 Plasma concentration time curves for 60 proxyphylline after administration of proxyphylline (135 mg/kg intravenous infusion over 5 minutes) in 6 rabbits. Figure Page 11.6 Typical plasma concentration time 62 curve for proxyphylline after administering proxyphylline (135 mg/kg by intravenous infusion over 5 min) in subject RR. III.la Plasma concentration time curves for 82 theophylline after admininstration of aminophylline (40 mg/kg intravenous infusion over 30 min) followed by dyphylline loading dose (300 mg/kg intravenous infusion over 8 min) and dyphylline maintenance dose (100 mg/kg/hr intravenous infusion over 2 hrs) in 6 rabbits. III.lb Plasma concentration time curves for 83 dyphylline after administration of aminophylline (40 mg/kg intravenous infusion over 30 min) followed by dyphylline loading dose (300 mg/kg intravenous infusion over 8 min) and dyphylline maintenance dose (100 mg/kg/hr over 2 hrs) in 6 rabbits. III.2a Plasma concentration time curves for 84 dyphylline after administration of dyphylline (300 mg/kg intravenous infusion over 8 min) followed by aminophylline (40 mg/kg intravenous infusion over 30 min) in 6 rabbits. III.2b Plasma concentration time curves for 85 theophylline after administration of dyphylline (300 mg/kg intravenous infusion over 8 min) followed by aminophylline (40 mg/kg intravenous infusion over 30 min) in 6 rabbits. III .3 Plasma concentration time curves for 86 theophylline (0) and dyphylline (V) after administration of aminophyline (40 mg/kg intravenous infusion over 30 minutes) followed by dyphylline loading dose (300 mg/kg intravenous infusion over 8 minutes) and dyphylline maintenance dose (100 mg/kg/hr intravenous infusion over 2 hours) in subject UU. Figure Page 111.4 Typical plasma concentration time 87 curves for theophyline (0) and dyphylline (7) after administration of dypylline (300 mg/kg intravenous infusion over 8 minutes) followed by aminophylline (40 mg/kg intravenous infusion over 30 minutes) in subject W. 111.5 Plasma concentration time curves for 94 dyphylline after administration of dyphylline (300 mg/kg intravenous infusion over 8 minutes) in 6 rabbits. 11.1.6 Typical plasma concentration time 95 curve for dyphylline after adminis- tering dyphyline by intravenous infusion over 8 min) in subject Z. IV.la Plasma concentration time curves for 118 etophylline after administering etophylline (150 mg/kg intravenous infusion over 5 minutes) followed by proxyphylline loading dose (135 mg/kg intravenous infusion over 5 minutes) and proxyphylline maintenance dose