Table Of ContentNicotine 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
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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
