Foreign Compound Metabolism in Mammals : Volume 2

D E Hathway

ISBN 10: 0851860184 / ISBN 13: 9780851860183

Verlag: Royal Society Of Chemistry Jan 1972, 1972

Beschreibung

Neuware - Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry. For over 80 years the Royal Society of Chemistry and its predecessor, the Chemical Society, have been publishing reports charting developments in chemistry, which originally took the form of Annual Reports. However, by 1967 the whole spectrum of chemistry could no longer be contained within one volume and the series Specialist Periodical Reports was born. The Annual Reports themselves still existed but were divided into two, and subsequently three, volumes covering Inorganic, Organic and Physical Chemistry. For more general coverage of the highlights in chemistry they remain a 'must'. Since that time the SPR series has altered according to the fluctuating degree of activity in various fields of chemistry. Some titles have remained unchanged, while others have altered their emphasis along with their titles; some have been combined under a new name whereas others have had to be discontinued. The current list of Specialist Periodical Reports can be seen on the inside flap of this volume.

Bestandsnummer des Verkäufers 9780851860183

Bibliografische Details

• Titel: Foreign Compound Metabolism in Mammals : Volume 2
• Verlag: Royal Society Of Chemistry Jan 1972
• Erscheinungsjahr: 1972
• Sprache: Englisch
• ISBN-10: 0851860184
• ISBN-13: 9780851860183
• Einband: Taschenbuch
• Zustand: Neu
• Abmessungen: 216B x 140 H x 30 T Millimeter Breite: 216 mm, Höhe: 140 mm, Tiefe: 30 mm
• Gewicht: 670 Gramm

Über diesen Titel

Inhaltsangabe

Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry. For over 80 years the Royal Society of Chemistry and its predecessor, the Chemical Society, have been publishing reports charting developments in chemistry, which originally took the form of Annual Reports. However, by 1967 the whole spectrum of chemistry could no longer be contained within one volume and the series Specialist Periodical Reports was born. The Annual Reports themselves still existed but were divided into two, and subsequently three, volumes covering Inorganic, Organic and Physical Chemistry. For more general coverage of the highlights in chemistry they remain a 'must'. Since that time the SPR series has altered according to the fluctuating degree of activity in various fields of chemistry. Some titles have remained unchanged, while others have altered their emphasis along with their titles; some have been combined under a new name whereas others have had to be discontinued. The current list of Specialist Periodical Reports can be seen on the inside flap of this volume.

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Foreign Compound Metabolism in Mammals Volume 2

A Review of the Literature Published in 1970 and 1971

By D. E. Hathway

The Royal Society of Chemistry

Copyright © 1972 The Chemical Society
All rights reserved.

ISBN: 978-0-85186-018-3

Contents

Foreword By D. E. Hathway, 
General Introduction By D. E. Hathway, 
Chapter 1 Tracers for Metabolism by I. P. Sword, 
Chapter 2 Transference of Radioactively Labelled Foreign Compounds By L. F. Chasseaud, 
Chapter 3 Biotransformations By D. E. Hathway, 
Chapter 4 Mechanisms of Biotransformation By D. H. Hutson, 
Chapter 5 Species, Sex, and Strain Differences in Metabolism By D. H. Moore, 
Chapter 6 Drug Kinetics By P. G. Welling, 
Chapter 7 Interactions of Drugs and Foreign Compounds By S. S. Brown, 
Compound Index, 475, 
Author Index, 493, 

CHAPTER 1

Tracers for Metabolism

BY I. P. SWORD

1 Introduction

This chapter is a review of organic synthetic methods using (mostly) low-energy [beta-]emitting radio-isotopes, and it deals largely with labelled compounds which have been synthesized for the elucidation of their metabolism in mammals. Many organic radiochemicals are synthesized for other purposes, but most of the labelled intermediates involved are potentially useful for metabolically oriented syntheses, and reference is made to them where appropriate. Some mention is also made of work with stable isotopes and, in passing, to reported improvements in some established radiochemical syntheses. Biologically mediated radiochemical syntheses have been excluded, since they have been reviewed earlier elsewhere, and are outside the scope of this review.

The literature coverage is for 1970 and 1971, although some information from 1969 is included, if it only became accessible (e.g., in Chemical Abstracts) in the following year. Although this chapter is not intended to be encyclopaedic, it is hoped that no major representative syntheses have been excluded. The reactions reported range from the relatively trivial to the complex.

It is encouraging to note that the editorial board of the Journal of Labelled Compounds intends to re-introduce a quarterly literature survey on publications involving work with isotopes, and to publish abstracts of all such work since 1966, when the service ended.

Investigations of the absorption, distribution, excretion, and biotransformation of foreign compounds are facilitated by the use of a radio-labelled form of the compound under study (see Vol. 1, p.34). Consequently, the link between radiochemistry and metabolic studies is well established. In fact, the metabolic fate of a compound is often accounted for in terms of radioactivity; (for limitations of the radiochemical method, see ref. 4).

General aspects of radiochemical synthesis, radiochemical purity, and the philosophy of using radiolabels in pharmacological and metabolic studies have been reviewed (see Vol. 1, p.36), as has the use of radio-isotopically labelled analytical reagents up to the end of 1969.

2 General Considerations

Choice of Nuclide and its Molecular Location. — A majority of metabolic studies are made with 14C as tracer. The relative cheapness of tritium, (brought about by military research) and the ease of its incorporation into molecules for study sometimes outweigh the disadvantages conferred by its potential lability under physiological conditions. When the economics of tritium labelling are compared with the alternative, often protracted 14C synthesis, the former is sometimes selected. However, caution must be exercised in the preparation and equilibration of tritium-labelled material before use, and in the interpretation of results, if useful information is to result.

Choice of molecular location for the tracer atom(s) primarily concerns syntheses with 14C, and to a lesser extent those with 3H. The site for labelling must be chosen to take the biological stability of the labelled part of the molecule and the cost of synthesis into consideration. A knowledge of the biotransformations of related molecules in mammals is essential to a proper consideration of which labelled form would give definitive information. Generally, only limited metabolic data are available from, for example, N-[14C]methyl or O-[14C]acetyl labelling, since in biological systems these groups may be dissociated from the main part of the molecule. Labelling in rings is preferable but normally expensive with 14C; even this has limitations as to its usefulness. The separate use of two or more labelled forms of the same material with the label in different molecular locations, or the incorporation of different radioactive nuclides in the same molecule constitute useful, but more expensive, methods for the more detailed monitoring of metabolites.

Sulphur-35 and phosphorus-32 have been used to some extent, but obviously give metabolic information only about molecular fragments containing these elements: there is normally no choice of molecular site for their incorporation. The amount of work with other nuclides in metabolic studies is relatively small.

Techniques of Syntheses with Isotopes. — The majority of reported organic syntheses with isotopes are undertaken on millimolar or larger quantities of material. For the synthetic chemist unfamiliar with techniques for handling small quantities of potentially hazardous material (often in vacuum-manifold systems), a number of reference texts are available. Probably the most useful general handbooks on the subject are those by Murray and Williams, Catch, and Evans. The series of reviews published in pamphlet form by the Radiochemical Centre, Amersham is indispensable. A review in Russian is also avai1able. Generally, a good radiochemical (or stable isotope) synthesis is a combination of a minimum number of high-yield synthetic steps involving the expensive labelled materials, and a minimum number of transfer and isolation procedures. Thus, the preparation of tracers for metabolism falls within the broad aims of organic synthesis, and some notable syntheses have been accomplished. Guidelines for the practical worker approaching radiochemical synthesis for the first time have been reported and the logistics of establishing and running a radio-synthesis unit discussed.

Specific Activity. — Tritium labelling has the advantage over, for example, 14C in that high specific activities are attainable at moderate cost, and this is particularly favourable for detection purposes when the mammalian dose of material under investigation is very low (e.g. with steroidal oral contraceptives). Specific activities with 32P and 35S generally exceed those attainable with 14C, which in turn normally exceed those attainable with 36Cl. One millicurie of product with a specific activity of 1 — 10 mCi mmol-l appears to be a convenient quantity for a normal metabolic study, but transport studies require material of high specific activity.

Radiochemical Purity and Autoradio1ysis. — Meaningful metabolic data can only be obtained from materials that are radiochemically pure, the criteria of radiochemical purity being quite distinct from those of chemical purity. However, in many of the papers reviewed in this chapter, no indication of the radiochemical purity or of the systems used to monitor it are given.

High specific activity materials and radiochemicals which have been stored for extended periods are particularly susceptible to radiation-induced decomposition...