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The Disposition of Morphine and Its 3- and 6-Glucuronide Metabolites in Humans

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The Disposition of Morphine and Its 3- and 6-Glucuronide Metabolites in Humans >+'è ,'i5 1. The Disposition of Morphine and its 3- and 6- Glucuronide Metabolites in Humans and Sheep A Thesis submitted in Fulfilment of the Requirements for the Degree of Doctor of Philosophy in Science at the University of Adelaide Robert W. Milne B.Pharm.(Hons), M.Sc. Department of Clinical and Experimental Pharmacology University of Adelaide August 1994 Ar,-,..u i.'..t itttlí I Corrigenda Page 4 The paragraph at the top of the page should be relocated to inimediatèly follow the section heading "1.2 Chemistry" on page 3" Page 42 (lines 2,5 and/) "a1-acid glycoProtein" should read "cr1-acid glycoprotein". Page 90 In the footnote "Amoxicillin" and "Haemacell" should read "Amoxycillin" and "Haemaccel", respectively. Page I 13 (tine -l l) "supernate!' should read "supernatant". ' '(j- Page I 15 (line -9) "supernate" should read "supernatalït1-. Page 135 To the unfinished sentence at the bottom of the page should be added "appears to be responsible for the formation of M3G, but its relative importance remains unknown. It was also proposed that morphine is involved in an enterohepatic cycle." Page 144 Add "Both infusions ceased at 6 hr" to the legend to Figure 6.3. Page 195 (line 2) "was" should fead "were". Page 198 (line l3) "ro re-€xamine" should read "to te-examine". Pages 245 to29l Bibliosraohv: "8r.." should read "Br.". For the reference by Bhargava et aI. (1991), "J. Pharmacol.Exp.Ther." should read "J. Pharmacol. Exp. Ther." For the reference by Chapman et aI. (1984), a full-stop should appear after"Biomed" . For the reference by Murphey et aI. (1994), a full-stop should appear after "pig". n negative line numbers should be read from the bonom of the page Contents Abstract IX Declaration xü Acknowledgements xüi Publications in Support of this Thesis xiv Abbreviations, Prefixes and Symbols xv Chapter L Morphine: a Review of the Literature 1 1.1 History of Morphine 1 r.2 Chemistry 3 1.2.I Structure 3 I.2.2. Physical and chemical properties of morphine, M3G and M6G 4 1.2.2.1 Morphine 4 1.2.2.2 M3G and M6G 6 1.2.2.3 Other Metaboliæs 7 r.3 Pharmacology of Morphine and its Metaboliæs 7 1 . 3. 1 Historical Development Of Opioid Pharmacology 8 1.3.2 Pharmacology of moqphine 10 1.3-2.1 Analgesia 11 I.3.2.2 Respiration 12 1.3.2.3 Gastrointestinal T3 1.3.2.4 Nausea and vomiting I4 I.3.2.5 Cardiovascular I4 I-3.2.6 Tolerance and dependence T4 1.3.3 Pharmacology of M6G t7 1.3.3.1 Animal studies L7 11 1.3.3.2 Human studies 22 1.3.4 Pharmacology of M3G 25 1.3.5 Pharmacology of Other Metabolites 29 l-4 Determination of Morphine and Metaboliæs in Biological Fluids 3r I-4.1 Radioimmunoassay 32 L.4.2 Gas-liquid Chromatography 34 1.4.3 High-Performance Liquid Chromatography 34 1.4.4 OtherMethods 37 1.5 Pharmacokinetics of Motphine 37 1.5.1 Absorption afær Oral Administration 38 1.5.2 Distribution 40 I.5.2.1 Binding in Plasma 4t 1.5.2.2 Distribution into Red Blood-Cells 42 I.5.2.3 Distribution into the Central Nervous System 42 I.5.2.4 Distribution to Other Tissues 45 1.5.3 Metabolism and Excretion 41 1.5.3.1 Metabolites and Excretory Profile 47 1.5.3.2 Sites of Metabolism 53 1.5.4 Elimination 57 I.5.4-1 Normal Hepatic and Renal Function 57 I.5.4.2 Hepatic Dysfunction 63 1.5.4.3 Renal Dysfunction 64 1.6 Pharmacokinetics of M3G and M6G 65 1.6.1 Human Studies 65 I.6.2 Animal Studies 69 1.7 Summary 70 111 Chapter 2 High-performance liquid chromatographic determination of morphine and its 3- and 6-glucuronide metabolites: improvements to the previous methods 2.t Introduction 72 2.2 Methods 73 2.2.1 Chemicals 73 2.2.2 Extraction of Moqphine, M3G and M6G from Plasma and Urine 74 2.2.3 HPLC Instrumentation and Conditions 75 2.2.4 Preparation of Calibration Standards 75 2.2.4.1 Plasma 75 2.2.4.2 Urine 76 2.2.4.3 Accuracy and Precision 76 2.2.5 Evaluation of Stability in Plasma and Urine 76 2.3 Results and Discussion 77 Chapter 3 The Influence of Renal Function on the Renal Clearance of Morphine and its Glucuronide Metabolites in Intensive Care Patients 3.1 Introduction 89 3.2 Methods 89 3.2.I Patients 89 3.2.2 Experimental Design 91 3.2.3 AnalyticalTechniques 9l 3.2.4 Studies of the Binding in Plasma 92 3.2.5 DataAnalysis 93 3.3 Results 94 3.4 Discussion 99 1V Chapter 4 Preparation of the Chronically-catheterized Sheep, and the Measurement of Physiological Parameters 4.r Introduction 105 4.2 Description of Sheep, Source and Maintenance 106 4.3 Induction of Anaesthesia 106 4.4 Placement of Catheærs 106 4.5 Induction of Renal Failure 110 4.6 Measurement of Flows t12 4.6.1 Cardiac Output l12 4.6.2 Hepatic Blood Flow 113 4.6.3 Renal Blood Flow 115 4.6.3.1 Fick Method 115 4.6.3.2 Doppler Flowmetry 116 Chapter 5 The Disposition of Morphine, M3G and M6G in the Sheep during Infusion with Morphine: Regional Elimination of Morphine and Regional Elimination and Formation of M3G and M6G 5.1 Introduction 119 5.2 Methods 119 5.2.1. Preparation of the Sheep 118 5.2.2 Experimental Design 119 5.2.3 Collection of Samples 119 5.2.4 Determination of Morphine, M3G and M6G 119 5.2.5 Determination of C6/C I20 V s.2.6 Equilibration of Morphine, M3G and M6G in Samples of Blood collected during Infusion with Morphine t20 5.2.7 Pharm ac okinetic Analysis I2I 5.2.8 Statistics r22 5.3 Results 122 5.4 Discussion 128 Chapter 6 Comparative Disposition of M3G during Separate i.v. Infusions of Morphine and M3G in Sheep: the Importance of the Kidney 6.1 Introduction 136 6.2 Methods r37 6.2.I Preparation of the Sheep r3l 6.2.2 Experimental Design t37 6.2.3 Collection of Samples 138 6.2.4 Binding of Morphine, M3G and M6G in Plasma 138 6.2.5 Deærmination of C6/C t39 6.2.6 Determination of Morphine, M3G and M6G r39 6.2.1 Determination of Creatinine in Plasma and Urine t39 6.2.8 Pharmacokinetic Analysis t40 6.2.9 Statistics r4t 6.3 Results t4r 6.3.I Profiles of the Concentrations in Plasma against Time r42 6.3.2 RegionalExtraction r45 6-3.3 Ratios of the Concentrations in Blood to Plasma (C/C) r46 6.3.4 Comparison of Total and Regional Clearances for Morphine and M3G r46 6.3.5 Binding in Plasma 147 6-3.6 Renal Clearance and Urinary Recovery 147 vl 6.3.7 Mass-balance across the Kidney and Liver t49 6.4 Discussion 150 Chapter 7 The Disposition of Morphine, M3G and M6G during i.v. Infusion of Morphine in Sheep and Comparison of the Disposition of M3G during Separate i.v. Infusions of Morphine and M3G: Studies in Sheep with Renal Failure 7.1 Introduction 160 7.2 Maærials and Methods 161 7 .2.1 Animal Preparation 161 7 .2.2 Experimental Design 161 7 .2.3 Collection of Samples r62 7.2.4 Binding of Morphine, M3G and M6G in Plasma r62 7.2.5 Determination of C6/C t62 7.2.6 Determination of Morphine, M3G and M6G 162 7 .2.7 Determination of Creatinine in Plasma and Urine 163 7 .2.8 Data Analysis 163 7.2.9 Statistics t64 7.3 Results 165 7.3.1 Concentrations in plasma-time profiles 168 7 -3.2 Regional Extraction r74 7 .3.3 Ratios of the Concentrations in Blood to Plasma (CdC) t76 7 .3.4 Comparison of Total and Regional Clearances for Morphine and M3G r77 7.3.5 Binding in Plasma n9 7 .3.6 Renal Clearance and Urinary Recovery t79 7 -3 -7 Mass Balance across the Liver 183 7.4 Discussion 184 vll Chapter I General Conclusion 194 Appendix 1 199 Appendix 2 202 Appendix 3 278 Appendix 4 229 Bibliography 245 vlll Abstract a Morphine is an opiate alkaloid used for the relief of severe pain. In man, it is eliminated predominantly by metabolism to morphine-3-glucuronide (M3G) and moqphine-6-glucuronide (M6G), which are excreted mainly in urine. There is considerable evidence that M6G has analgesic activity in humans and animals, and that M3G is a functional antagonist of some of the pharmacological actions of morphine and M6G. a To examine the disposition of morphine and its 3- and 6-glucuronide metabolites in humans and sheep, an improved HPLC method was developed to measue the concentrations of the three compounds in plasma and urine. The stability of the compounds during storage in plasma was also established. a The influence of renal function on the renal clearance of morphine, M3G and M6G was examined in patients receiving morphine by continuous i.v. infusion while under intensive- care. There were significant linear relationships between renal function, measured by the renal excretory clearance of creatinine, and the renal clearances of morphine, M3G and M6G. There was evidence for the net secretion of morphine by the kidney, but there was no net secretion or reabsorption of M3G and M6G.
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