Table Of ContentA Specialist Periodical Report
~
Foreign Compound Metabolism
in Mammals
Volume 2
A Review of the Literature Published
in 1970 and 1971
Senior Reporter
D. E. Hathway, Department of Chemistry, University of
Essex, Colchester
Reporters
S. S. Brown, MRC Clinical Research Centre, Harrow
L. F. Chasseaud, Huntingdon Research Centre, Huntingdon
D. H. Hutson, Shell Research Limited, Sittingbourne, Kent
D. H. Moore, Huntingdon Research Centre, Huntingdon
1. P. Sword, Huntingdon Research Centre, Huntingdon
P. G. Welling, School of Pharmacy, University of Wisconsin,
Madison , Wisconsin, U.S.A.
0 Copyright 1972
The Chemical Society
Burlington House, London, WIV OBN
1
ISBN : 0 85186 018 4
Printed by Eyre & Spottiswoode Ltd, Thanet Press, Margale
Fore word
Volume 2 of ‘Foreign Compound Metabolism in Mammals’ covers the two-
year period 1970,1971,a nd it is planned that henceforth this series of Specialist
Periodical Reports will be issued biennially. Chapters on the synthesis of
Tracers for Metabolism, on the Transference of Foreign Compounds, on
Biotransformations, on Mechanisms of Biotransformation, on Species, Strain,
and Sex Differences in Metabolism, on Drug Kinetics and on Drug Inter-
actions follow a logical pattern. The first three Chapters and Chapter 5 on
Species, Strain, and Sex Differences in Metabolism aim at complete coverage
of the literature for the two-year period. In Chapter 4, the main objectives
are precise information about enzymically catalysed reaction processes and
about the mechanism of induction of the drug-metabolizing enzymes.
Peripheral communications, involving work with inappropriate test systems
which may, however, reveal the sites of biotransformation, have been
precluded, since they do not contribute to the elucidation of those mechan-
isms. The aim of Chapter 6 onDrug Kinetics is thedevelopmento f mathemat-
ical approaches, which afford valuable infomation about, for example, the
biological availability of a drug, its rate of absorption, the distribution volume,
the rate of elimination from circulating blood, aspects of renal clearance,
important rate constants of unit and functional processes, etc. There is a great
deal of relevant material, but papers about other aspects of metabolism which
may contain a few blood levels often expressed in term of radioactivity do not
fall within the scope of this specialist chapter. Such information is in fact
referred to in the Chapter 2, about Transference. Chapter 7 is concerned only
with authenticated Drug Interactions, capable of systematic explanation, and
the possible explanations for such interactions are strictly limited. Part of
this chapter has been written from the viewpoint of those drugs, which are
known to be associated with important interactions.
Novel features of the second volume on ‘Foreign Compound Metabolism
in Mammals’ are the inclusion (i) of six Memoranda, which deal with some
implications of Metabolic Studies with regard to toxicology and medicine,
in a General Introduction, and (ii) of a Compound Index. In his Preface
to the fist volume, Professor Barton observed that these volumes provide a
unique opportunity for assessing the scope and limitation of existing method-
ology and basic thinking in the field of foreign-compound metabolism, and
those Memoranda have been written from that viewpoint. Thus, the article
‘Validation in Man’ examines how the confirmation in man of the metabolic
data found in animals might be realized. The memorandum on ‘Biological
Availability’ probes the meaning of those terms and the significance of that
concept. In the safety evaluation of drugs and pesticides, toxicity testing is
iv Foreword
very important and expensive, and the article on ‘The Selection of Animals
for Long-term Toxicity Testing’ strongly recommends that comparative drug
metabolism studies in animals and in man ought to be fundamental to this
selection process. Similar basic thinking underlies ‘The Implications of
Metabolic Studies on the Determination of No-effect Levels’, where the
context is man and his diet. Drug Metabolism studies have widespread appli-
cation in medicine, and the fields of addiction and cardiology are the ones on
which the ‘Novel Methods for the Measurement of Low PIasma Concentra-
tion of Drugs’ impinge. ‘Perspectives in Toxicology’ draws attention parti-
cularly to the current problems of mutagenicity. Encouraged by reports from
experts in different countries, who are engaged in the metabolic and toxi-
cological evaluation of foreign compounds, it was felt that this series of
Specialist Periodical Reports would be more widely useful as works of
reference within the pharmaceutical and chemical industry, if each volume
was provided with a Compound Index. It is therefore a pleasure to thank the
Director of Publications of The Chemical Society, Dr. L. C. Cross, and the
Editor, Reports and Reviews, Philip Gardam, for their sympathetic help in
what represents a departure from existing policy for Specialist Periodical
Reports in general. Volume 2, in fact, contains an Index of the drugs, food
additives, pesticides, etc. for Volumes 1 and 2.
Although no separate consideration is given in the second volume to
possible biotransformation of a foreign compound into biologically active
metabolites, it is intended to specifically discuss the matter of bioactivation
and detoxication in a subsequent volume. In the present volume, occurrences
of bioactivation are of course mentioned in Chapter 3 on Biotransformations.
In fact, the discovery that the main biological activity of a foreign compound
may be due to or modified by its metabolites, constitutes a major stimulus to
the identification of the metabolitts of new foreign compounds. Thus, con-
siderable hypotensive activity is associated with the trinitro-metabolite of
pentaerythrityl tetranitrate, two metabolites (N-demethyldiazepam and
oxazepam) probably contribute to the anti-convulsant properties of diazepam
(Valium), and three metabolites (diazepam, N-demethyldiazepam, and
oxazepam) to the sedative, muscle relaxant, and anti-convulsant activities of
medazepam. In the treatment of Parkinson’s disease, L-dopa is a vehicle for
a biologically active amine. Fenetylline and cloforex owe their pharmacologi-
cal actions to their major metabolites, amphetamine plus theophylline or
chloi phentermine, respectively. Several metabolites of imipramine modulate
its central anti-depressant action; the carcinogenic action of several classes of
carcinogens is probably due to their action as electrophilic reagents; the
carcinogenic action of 2-p-methoxybenzenesuIphonamido-5-isobutyl-l,3,4-
thiadiazole seems to be due to bioactivation into the primary alcohol and
carboxylic acid, formed by the hydroxylation and oxidation of one of the
methyl groups belonging to the isobutyl side-chain. 3-Nitropropan-1-01 is
the major toxic metabolite of miserotoxin, the timber-milk vetch. P -+ 0 meta-
bolites of dimethoate are one thousand-fold more powerful cholinesterase
-
Foreword V
inhibitors than the P S compounds; metabolites of phosphamidon are
equitoxic or more toxic than the biocide per se; and the metabolic pathway
of styrene involves an initial bioactivation associated with epoxidation.
Finally, we should like to add a short list of relevant books and reviews:
Conference on ‘Drug Metabolism in Man’, held by The New York
Academy of Sciences duiing June 29-July 1, 1970, and reported in
Ann. New York Acad. Sci., 1971, 179, 1-773, ed. E. S. Vesell.
B. N. La Du, H. G. Mandel, and E. L. Way, ‘Fundamentals of Drug
Metabolism and Drug Disposition, The Williams & Wilkins Company,
Baltimore, 1971.
B. B. Brodie and J. R. Gillette, ‘Concepts in BiochemicalPharmacology’,
vo1.28/1 of Heffter-Heuber ‘Handbuch der experimentellen Pharmakolo-
gie, ed. 0. 0. Eichler, A. Farah, H. Herken, and A. D. Welch, Springer
Verlag, Berlin, Heidelberg, and New York, 1971.
J. Hirtz, ‘Le Sort des Medicaments dans I’Organisme’, Masson and
Cie, Paris, 1970, 2 vols.
F. J. C. Roe, ‘Metabolic Aspects of Food Safety’, Blackwells, Oxford,
1970.
P. C. Kearney and D. D. Kaufman, ‘Degradation of Herbicides’, Marcel
Dekker, New York, 1969.
H. Matthew, ‘Acute Barbiturate Poisoning’, Excerpta Medica, Amster-
dam, 1971.
Report on the proceedings of an International Conferencx on ‘Alternative
Insecticides for Vector Control’, Bull. World Health Organ., 1971, 44,
issues 1-3 (combined).
R. D. O’Brien and I. Yamamoto, ‘Biochemical Toxicology of Insecti-
cides’, Academic Press, New York, and London, 1970.
E. C. Amoroso, ‘Report of the Nato Conference/Alberta 1970/on
Toxicology of Pesticides’, 1971.
G. Rasp&, ‘Advances in the Biosciences 5, Schering Workshop on
Pharmacokinetics, Berlin, 1969’, Pergamon Press and Vieweg, Oxford
and Braunschweig, 1970.
P. Viars and J. Seebacher Arnette, ‘Les Interfbrences medicamenteuses’,
Paris, 1971.
E. A. Hartshorn, ‘Handbook of Drug Interactions’, Donald E. Francke,
Cincinnati, 1970.
G. Swidler, ‘Handbook of Drug Interactions’, Wiley-Interscience, New
York, 1971.
P. D. Hansten, ‘Drug Interactions’, Lea and Febiger, Philadelphia, 1970.
A. Burger, ‘Medicinal Chemistry’, part 1 (835 pp.), part 2 (1181 pp.),
3rd edn., Wiley-Interscience, Chichester, New York, Toronto, and
Sydney, 1970.
E. Mutschler, ‘Ameimittelwiikungen’, Stuttgart Wissenschaftliches
Verlagsgesellschaft, 1970.
vi Fore word
An excellent Report of a W.H.O. Study Group on Clinical Pharmacology,
W.H.O.T echnical Report Series, no. 446, Geneva, 1970, might influence
career development.
I should like to thank the Chairman of Huntingdon Research Centre, Dr.
A. N. Worden, for his support, my former Secretary, Mrs. Pamela J.
Deacon, for her indefatigable help, and the Librarian, Miss Margaret G.
Shafto, for help with the literature retrieval.
D. E. Hathway
October 1972
Contents
Fore word
By D. E. Hathway
General Introduction
By D. E. Hathway
1 Validation in Man 1
2 Biological Availability 2
3 The Selection of Animals for Long-term Toxicity Testing 5
4 The Implications of Metabolic Studies on the
Determination of ‘No-effect Levels’ 7
5 Novel Methods for the Measurement of Low Plasma
Concentrations of Drugs 8
6 Perspectives in Toxicology 10
Chapter 1 Tracers for Metabolism
by I. P. Sword
1 Introduction 13
2 General Considerations 14
Choice of Nuclide and its Molecular Location 14
Techniques of Syntheses with Isotopes 14
Specific Activity 15
Radiochemical Purity and Autoradiolysis 15
Labelled Precursors 16
Nomenclature 16
Arrangement of Material 17
viii Contents
3 Syntheses with 3H, 14C, 32P, and W l 17
4 Syntheses with Other Radioisotopes 56
5 Reactions of a General Nature '58
6 Stable Isotopes 60
Chapter 2 Transference of Radioactively Labelled Foreign
Compounds
By L. f. Chasseaud
1 Introduction 62
2 Drugs 64
Alimentary System 64
Cardiovascular System 66
Cardiac Glycosides 66
Nitrates 68
Other Drugs 69
Central Nervous System 75
Analgesics 75
Anti-inflammatory Agents 80
Hypnotics 82
Sedatives and Tranquillizers 83
Anticonvulsants 91
Rigidity and Tremor Controllers 92
C.N.S. Stimulants 93
Muscle Relaxants 93
Antihistamines 95
Antidepressives 95
Ant i-emeti cs 97
Hallucinogens 98
Endocrine Drugs 100
Genit o-urinary Sys tem 103
Urinary Antiseptics and Antispasmodics 103
Diuretics 105
Drugs Acting on Infections 105
Antibiotics 105
Sulphonamides 109
Antituberculosis Drugs 109
Other Compounds 110
Nutrition and Metabolism 113
Hypoglycaemic Agents 113
Antithyroid Preparations 114
Anti-obesity Agents 114
Hypolipaemic Agents 116
Carcino-chemot h efapeuti c Agents 117
