Nicotine and Related Alkaloids: Absorption, distribution, metabolism and excretion PDF
Preview Nicotine and Related Alkaloids: Absorption, distribution, metabolism and excretion
Nicotine and Related Alkaloids Nicotine and Related Alkaloids Absorption, distribution, metabolism and excretion Edited by J.W. Gorrod Chelsea Department of Pharmacy King's Col lege, London, UK and J. Wahren Department of Clinical Physiology Karolinska Institute, Stockholm, Sweden 1~lll SPRJNGER-SCIENCE+BUSINESS MEDIA, B.V. First edition 1993 © 1993 Springer Science+Business Media Dordrecht Originally published by Chapman & Hali in 1993 Typeset in 10/12 Palatino by Acom Bookwork, Salisbury, Wiltshire ISBN 978-94-010-4936-8 ISBN 978-94-011-2110-1 (eBook) DOI 10.1007/978-94-011-2110-1 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the UK Copyright Designs and Patents Act, 1988, this publication may not be reproduced, stored, or transmitted, in any form or by any means, without the prior permission in writing of the publishers, or in the case of reprographic reproduction on1y in accordance with the terms of the licences issued by the Copyright Ucensing Agency in the UK, or in accordance with the terms of licences issued by the approppate Reproduction Rights Organization outside the UK. Enquiries conceming reproduction outside the terms stated here should be sent to the publishers at the London address printed on this page. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that maybemade. A catalogue record for this book is available from the British Ubrary Ubrary of Congress Cataloging-in-Publication data available I§ Printed on permanent acid-free text paper, manufactured in accordance with the proposed ANSI/NISO Z 39.48-199X and ANSI/ NISO Z 39.48-1984 Dedication This volume is dedicated to the fond memory of Professor Herbert (Herb) McKennis and Professor Edward (Ed) Leete with much affection. Herb and Ed greatly influenced our thinking on the degradation and biosynthesis of nicotine and related alkaloids. Herb McKennis, together with his colleagues in the Department of Pharmacology at the Medical College of Virginia, undertook pioneering studies on the metabolism of nicotine in mammals. The state of the art in analytical techniques in the 1960s gave rise to many problems of detection associated with elucidating the metabolic pathways of a highly toxic substance. Not for Herb the transient response of a recor der indicating the presence of a compound; he would insist on isolating the metabolite in crystalline form and fully characterizing the urinary metabolite or a derivative and comparing its properties with synthetic material. From these data he proposed metabolic pathways and con firmed them by administering the putative metabolites. In this way, a complex picture of nicotine metabolism has emerged which only now, with the advent of radiolabelling and other techniques, have we begun to probe. Herb laid down the foundation on which the contributors to this volume have been proud to build. Ed Leete was English by birth and university training, but soon moved to Canada and from there to the USA. After a brief stay in Cali fornia, in 1958 he moved to the University of Minnesota where he rose to become full Professor. Ed was a classical chemist who applied his eminent talent to problems on biosynthesis in plants. Ed would admin ister potential precursors to the plant, allowing it to grow and then isolate the alkaloid from plant material. If the radiolabel had been incorporated clearly, the administered compound was a precursor. This then required the position of the label in the isolated material to be established by painstaking experimental degradation procedures. From these data Ed was able to propose biosynthetic pathways and test his ideas by further experiments using the proposed intermediates until a vi Dedication full biosynthetic map was constructed. Ed then used these pathways to obtain unnatural analogues of plant alkaloids which had some potential as medicinal agents. Both Herb and Ed were very quiet, modest scientists who willingly gave of their knowledge and expertise; both had the knack of encoura ging, and never putting down. It was a pleasure to be in their company and their contributions to 'nicotine' science and life will long be remem bered. Professor H. McKennis Professor E. Leete 1916-1983 1918-1992 Contents Contributors xi Preface xv Acknowledgements xvii 1 Biosynthesis and metabolism of nicotine and related alkaloids 1 L.P. Bush, F.P. Fannin, R.L. Chelvarajan and H.R. Burton 1.1 Introduction 1 1.2 Alkaloid biosynthesis 3 1.3 Regulation of nicotine content in tobacco plants 10 1.4 Alkaloid transformations during senescence and curing 17 Acknowledgement 25 References 25 2 The mammalian metabolism of nicotine: an overview 31 J.W. Gorrod 2.1 Introduction 31 2.2 Primary carbon oxidation products of nicotine 32 2.3 The metabolism of cotinine 34 2.4 The metabolism of nornicotine 36 2.5 The metabolism of 4-(3-pyridyl)-4-oxobutyric acid 38 2.6 The N-oxidation of nicotine 39 2.7 Methylation reactions of nicotine and cotinine 39 2.8 Conjugation reactions 39 2.9 Conclusions 40 Acknowledgement 40 References 40 3 The roles of cytochrome P450 in nicotine metabolism 45 H. Nakayama, T. Kita, T. Nakashima, S. Imaoka and Y. Funae 3.1 Introduction 45 viii Contents 3.2 Mechanisms of cotinine formation 46 3.3 Forms of cytochrome P450 participating in hepatic microsomal nicotine oxidation 48 3.4 Regulation of cytochrome P450 dependent nicotine . metabolism 54 Acknowledgements 56 References 56 4 Nicotine metabolism beyond cotinine 61 G.B. Neurath 4.1 Introduction 61 4.2 Oxidation of nicotine 63 4.3 Metabolism of cotinine 67 4.4 Conclusions 75 References 76 5 N-Oxidation, N-methylation and N-conjugation reactions of nicotine 81 P.A. Crooks 5.1 Introduction 81 5.2 N-Oxidation reactions of nicotine 82 5.3 N-Methylation reactions of nicotine 91 5.4 Glucuronidation reactions of nicotine 96 5.5 Nicotinamide nucleotide analogues of nicotine and cotinine 103 References 105 6 Extrahepatic metabolism of nicotine and related compounds by cytochromes P450 111 K. Viihiikangas and o. Pelkonen 6.1 Introduction 111 6.2 Pathways and enzymes of nicotine metabolism 112 6.3 Cytochrome-P450 isozyme specificity of nicotine metabolism 113 6.4 Extrahepatic metabolism of nicotine in relation to the localization of enzymes potentially participating in nicotine metabolism 115 6.5 Extrahepatic activation of tobacco-specific nitrosamines 119 6.6 Contribution of extrahepatic metabolism to the pharmacokinetics and toxicity of nicotine and related compounds 121 6.7 Unanswered important questions and suggestions for future work 122 6.8 Conclusions 123 References 123 Contents ix 7 The metabolic fate of the minor tobacco alkaloids 129 X. Liu, P. Jacob III and N. Castagnoli Jr 7.1 Introduction 129 7.2 The metabolic fate of cotinine 130 7.3 ~-Nicotyrine 133 7.4 Other minor tobacco alkaloids 141 Acknowledgement 142 References 142 8 Nicotine and metabolites: analysis and levels in body fluids 147 M. Curvall and E. Kazemi Vala 8.1 Introduction 147 8.2 Nicotine and cotinine 148 8.3 3'-Hydroxycotinine 160 8.4 Glucuronic acid conjugates of nicotine, cotinine and trans-3'-hydroxycotinine 164 8.5 N-Oxides of nicotine and cotinine 165 8.6 N-Methylated derivatives of nicotine and cotinine 168 8.7 Nor- derivatives of nicotine and cotinine 169 8.8 Summary 170 References 172 9 Kinetics of nicotine and its metabolites in animals 181 J. Gabrielsson and M. Gumbleton 9.1 Introduction 181 9.2 Absorption kinetics and first-pass metabolism 184 9.3 Disposition kinetics 186 References 193 10 Pharmacokinetics of (S)-nicotine and metabolites in humans 197 P. Jacob III and N. Benowitz 10.1 Introduction 197 10.2 Stable isotope methodology 198 10.3 Synthesis of labelled nicotine and metabolites 199 10.4 Analytical methodology 202 10.5 Pharmacokinetics of (S)-nicotine-3',3'-d 202 2 10.6 Pharmacokinetics of nicotine in smokers and nonsmokers 204 10.7 Bioavailability studies 207 10.8 Urinary excretion of nicotine metabolites 209 10.9 Pharmacokinetics of cotinine formation and elimination 210 10.10 Future studies 213 10.11 Conclusion 214 Acknowledgements 215 References 215 x Contents 11 Sources of inter-individual variability in nicotine pharmacokinetics 219 S. Cholerton, N.W. McCracken and J.R. Idle 11.1 Introduction 219 11.2 Absorption of nicotine 219 11.3 Distribution of nicotine 222 11.4 Metabolism of nicotine 224 11.5 Excretion of nicotine 243 11.6 Implications of inter-individual variability in nicotine pharmacokinetics 244 Acknowledgements 245 References 245 12 Physiologically based pharmacokinetic modelling of nicotine 255 S.L. Schwartz, M.R. Gastonguay, D.E. Robinson and N.J. Balter 12.1 Physiologically based pharmacokinetic modelling 255 12.2 Potential utility of a PBPK model of nicotine 256 12.3 Development of the PBPK model of nicotine and cotinine in humans 257 12.4 Application of a multi-metabolite PBPK model of nicotine to exposure assessment 262 12.5 Low level nicotine exposure model 264 12.6 PBPK and nicotine pharmacodynamics 266 12.7 Summary 271 Acknowledgements 271 References 272 13 New methods for probing the disposition of nicotine in humans 275 J. Wahren, J. Gabrielsson, M. Curvall and E. Kazemi Vala 13.1 Introduction 275 13.2 Regional catheterization 276 13.3 Positron emission tomography (PET) 280 13.4 Nuclear magnetic resonance (NMR) techniques 281 References 282 Index 285 Contributors N.J. Balter N. Castagnioli Jr Department of Pharmacology Department of Chemistry Georgetown University School of Virginia Polytechnic Institute Medicine and State University 3900 Reservoir Road NW Blacksburg, VA 24061-0212 Washington DC 20007 USA USA R.L. Chelvarajan N. Benowitz Department of Agronomy Departments of Medicine and University of Kentucky Psychiatry Lexington, KY 40546-0091 Division of Clinical Pharmacology USA San Francisco General Hospital Medical Center S. Cholerton University of California Pharmacogenetics Research Unit San Francisco, CA 94110 Department of Pharmacological USA Sciences The Medical School H.R. Burton The University Department of Agronomy Newcstle upon Tyne NE2 4HH University of Kentucky UK Lexington, KY 40546-0091 USA P.A. Crooks College of Pharmacy L.P. Bush University of Kentucky Department of Agronomy Lexington, KY 40536-0091 University of Kentucky USA Lexington, KY 40546-0091 USA M. Curvall Reserca AB 5-11884 Stockholm Sweden
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