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The Elimination of High Doses of Phenytoin In THE ELIMINATION OF HIGH DOSES OF PHENYTOIN IN MAN AND THE RABBIT by Peter Chinwah Department of Clinical Pharmacology St. Vincent's Hospital Darlinghurst, 2010, N.S.W. AUSTRALIA A Thesis submitted for the Degree of Master of Science in the University of New South Wales February, 1987 Ul·lilJ:2?.S1TY QF N.S.W. ~ 14 JUN 1988 f L!.:.": --":c_A:_'''"lARY I (i) ACKNOWLEDGEMENTS I wish to thank Professor Denis Wade for the opportunity to undertake this thesis in the Department of Clinical Pharmacology and for his overseeing and supervision of this project. I would like to express my gratitude to Dr Garry Graham, Senior Lecturer in the Department of Physiology and Pharmacology at the University of New South Wales, for his significant contribution in discussion and critical review of this thesis. I also wish to thank my colleagues of the Department of Clinical Pharmacology and Toxicology at St Vincent's Hospital for their assistance during the course of the project. Finally, I am grateful to Dr Ken Williams of the Department of Clinical Pharmacology and Toxicology at St Vincent's Hospital for many hours of discussion, and his admonishment, long suffering and perserverence which have made this thesis possible. (ii) ABSTRACT The pharmacokinetics of phenytoin were studied in twelve patients who presented to casualty with phenytoin toxicity. These patients were divided into 3 groups according to the type of plasma elimination profiles observed. Group 1. consisted of 3 patients who demonstrated first order elimination kinetics with long elimination half lives (70-106 hours). Group 2. consisted of 6 patients who showed saturable elimination kinetics (mean estimated terminal half life 28 hours). In Group 3. there were 3 patients who had "plateau" or rising plasma concentrations lasting from 2.5 - 14 days. It was thought that the rises and plateaus of plasma concentrations could be due to a) absorption and/or b) redistribution within body compartments. The data demonstrates the large interpatient variability in the disposition of phenytoin following overdose. Clearly, the disposition of therapeutic doses of phenytoin cannot be used as a predictor of the time course of events following an overdose of the drug. The factors leading to the plateau plasma concentrations were further investigated by studying the disposition of phenytoin in the rabbit. It was established that at a dosage of 74 mg/kg I.V. the plasma concentrations of phenytoin at first fell rapidly but then reached a plateau phase similar to that observed in man. During this plateau phase there was a significant relative change in phenytoin distribution (iii) into fat when compared with a single therapeutic dose. There was 5.5% in fat following the low dose but 10-20% following the high dose. This data suggests that redistribution of phenytoin from fat back into plasma may be one of the factors contributing to the plateau of plasma concentrations seen in some patients following an overdose. The protein binding of phenytoin was studied in the patients who had taken an overdose of the drug. Free fractions of phenytoin when first admitted and when plasma concentrations had returned to non-toxic concentrations were not significantly different. In contrast, however, there was a higher free fraction of phenytoin in plasma taken from rabbits given high doses of phenytoin as compared with those given a low dose. In this respect, the concentration dependent changes in protein binding in rabbits may contribute to the profiles observed, more so than in humans. Transient hypotension has been reported in man after both I.V. and oral administration of phenytoin. An overall hypotensive effect of large doses of phenytoin was observed in rabbits. However, these changes in blood pressure were not sufficient to have an effect on the clearance of phenytoin. Liver blood flow was not decreased by large doses of phenytoin. It is unlikely that hypotensive effects of phenytoin significantly alter its disposition following overdose in man. Large doses of phenytoin may not always result in toxic plasma concentrations. Some patients were found to require large doses of phenytoin for adequate control of their epilepsy. Short half (iv) lives in these patients may be attributed to the effects of enzyme induction by other drugs taken concurrently. However, some people may be rapid metabolizers of phenytoin, although this could not be unequivocally demonstrated in these patients. Patients who cleared phenytc:n rapidly did not necessarily clear other anticonvulsants rapidly. Epileptics with rapid metabolism of phenytoin may be better controlled by using a different anticonvulsant such as carbamazepine. (v) PREFACE Much of the work of this thesis has been published and/or presented at meetings of the Australasian Society of Clinical and Experimental Pharmacologists. During the course of the thesis, was involved in other projects which resulted in a number of publications which are also listed below: Publications Supporting this Thesis (1) Phenytoin, phenobarbitone and carbamazepine elimination kinetics in overdosed patients. P.M. Chinwah, D.N. Wade and K.M. Williams, Clin. Exp. Pharmacol. Physiol., 8, 653, 1981. (2) A study of the distribution and elimination of high doses of phenytoin in rabbits. P.M. Chinwah, D.N. Wade and K.M. Williams. Clin. Exp. Pharmacol. Physiol., 8, 459-60, 1982. (3) Macrodosage of phenytoin. G.G. Meredith, M. Kennedy, P.M. Chinwah and D.N.Wade. Med. J. Aust., 2, 584, 1979. ( 4) Multiple drug interactions with phenytoin. D. J. Birkett, G.G. Graham, P.M. Chinwah, D.N. Wade and J.B. Hickie, Med. J. Aust., 2, 467, 1977. (vi) Other Publications (5) Monitoring plasma concentrations of drugs. G.G. Graham, P.M. Chinwah, M. Kennedy and D.N. Wade. Med. J. Aust., 2, 124, 1980. (6) Enhanced metabolism of mexiletine after phenytoin adminstration. E.J. Begg, P.M. Chinwah, C. Webb, R.O. Day and D.N. Wade. Br. J. Clin. Pharmacol., 14, 219-223, 1982. (7) A pharmacological method of measuring mouth-caecal transit time in man. M. Kennedy, P.M. Chinwah and D.N. Wade, Br. J. Clin. Pharmacol., 8, 372-373, 1979. (8) The measurement of mouth-caecal transit time using salicylazosulphapyridine. E. J. Begg, M. Kennedy, P.M. Chinwah and D.N. Wade. Clin. Exp. Pharmacol. Physiol., 7, 639-691, 1980. (9) Comparison of enzyme immunoassay for gentamicin compared with other methods. P.M. Chinwah and K.M. Williams, J. Antimicrob. Chemotherap., 6, 561-562, 1980. (10) Chlorbutol toxicity and dependence. T. Borody, P.M. Chinwah, G.G. Graham, D.N. Wade and K.M. Williams, Med. J. Aust., 1, 288, 1979. (11) Crystalluria during flucytosine therapy. K.M. Williams, P.M. Chinwah and R. Cobcroft. Med. J. Aust., 2, 617, 1979. (vii) ABBREVIATIONS AUC area under plasma concentration versus time curve BP blood pressure CL clearance EMIT enzyme immunoassay technique HPPH p-hydroxyphenyl phenylhydantoin ICG indocyanine green GLC gas liquid chromatography t 1 / 2 half-life of elimination volume of distribution TABLE OF CONTENTS Page ACKNOWLEDGEMENTS (i) ABSTRACT (ii) PREFACE (Publications supporting this Thesis) (v) ABBREVIATIONS (vii) CHAPTER 1 INTRODUCTION 1 .1 General Introduction - Michaelis-Menten Kinetics 1. 1.2 The Absorption of Phenytoin 5. 1.3 The Disposition of Phenytoin 6. 1.3.1 Binding and Distribution 6. 1.3.2 Metabolic Clearance 9. 1.4 The Disposition of Phenytoin Following an 12. Overdose 1.4.1 General 12. 1.4.2 Absorption 12. 1.4.3 Binding and Distribution 13. 1.4.4 Metabolic Clearance 14. 1.5 Some Specific Factors Affecting the Metabolism 15. of Phenytoin 1.5.1 General 15. 1.5.2 Drug Interactions {Enzyme Induction) 18. 1.5.3 Effects of Alcohol on the Metabolism of 19. Phenytoin 1.5.4 Genetic Effects on Phenytoin Metabolism 20. 1.5.5 Effects of Liver Disease on Metabolism 20. 1.6 Aims of Present Study 21. CHAPTER 2 MATERIALS AND METHODS 2.1 Materials 23. 2.1.1 Chemicals 23. 2.1.2 Instruments and Hardware 23. 2.1.3 Rabbits 25. 2.2 Sampling schedules 25. 2.2.1 Overdose Patients 25. 2.2.2 Rapid Metabolizers of Phenytoin 25. 2.2.3 Low Dose Pharmacokinetic Studies with 26. Rabbits 2.2.4 High Dose Pharmacokinetic Studies in 26. Rabbits 2.2.5 Blood Pressure Experiments in Rabbits 26. 2.2.6 Tissue Distribution Studies in Rabbits 26. 2.3 Analytical Methods and Procedures for Human 27. Studies 2.3.1 Enzyme Multiple Immunoassay Technique 27. (E.M.I.T.) 2.3.2 Overdose Patients 27. 2.3.3 Rapid Metabolizers of Phenytoin 28. 2.3.4 Alcohol Estimations 29. 2.3.5 Protein Binding Determinations 30. 2.4 Analytical Methods and Procedures for Animal 30. Studies 2.4.1 Low and High Dose Pharmacokinetics 30. 2.4.2 Phenytoin Tissue Distribution Studies 31. 2.4.3 The Effect of High Doses of Phenytoin on 32. Blood Pressure in Rabbits 2.4.4 Hepatic Blood Flow in Rabbits 33. 2.4.5 Estimation of Phenytoin Concentrations 34. Bile 2.4.6 Estimation of Phenytoin Concentrations 34. in Fat 2.4.7 GLC Assay for HPPH 35. 2.5 Pharmacokinetic Analysis of Data 35. CHAPTER 3 RESULTS 3.1 Overdosed Patients 38. 3.2 The Pharmacokinetics of Phenytoin Elimination 48. in Rabbits 3.3 Distribution of Phenytoin into Tissues 56. 3.4 The Protein Binding of Phenytoin in Man and 69. Rabbits 3.5 Effects of Phenytoin on Blood Pressure in Rabbits 75. 3.6 Effects of Phenytoin on Liver Blood Flow in the 81. Rabbit 3.7 Rapid Metabolisers of Phenytoin 86. 3.8 Reliability of Phenytoin Estimations by E.M.I.T. 94. CHAPTER 4 DISCUSSION 4.1 Phenytoin Overdosed Patients 99. 4.1.1 Apparent First Order Elimination Kinetics 99.
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