Mass Spectrometry in Drug Metabolism

526 Pages·1977·13.21 MB·English

by  A. Donetti, L. G. Dring, P. C. Hirom, R. T. Williams (auth.), Alberto Frigerio, Emilio L. Ghisalberti (eds.)

moss Spectrometr.Y
Drug
in rTletobolism
moss
Spectrometry
in Drug fTletobolism
Edited by
Alberto Frigerio
"Mario Negri" Institute for Pharmacological Research
Milan, Italy
and
Emilio L. Ghisalberti
Department of Organic Chemistry
University of Western Australia
Nedlands, Western Australia
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
International Symposium on Mass Spectrometry in Drug Metabolism, Mario Negri
Institute, 1976.
Mass spectrometry in drug metabolism.
"Proceedings of an International Symposium on Mass Spectrometry in Drug
Metabolism held at the 'Mario Negri' Institute for Pharmacological Research, June,
1976."
Includes index.
1. Drug metabolism-Congresses. 2. Drugs-Analysis-Congresses. 3. Mass spectrom
etry-Congresses. I. Frigerio, Alberto. II. Ghisalberti, Emilio L. III. Title. [ON LM:
1. Spectrum analysis, Mass-Congresses. 2. Drugs-Metabolism-Congresses. 3. Drugs
Analysis-Congresses. 4. Drug abuse-Congresses. OV38 160Sm 1975)
RM301.IS71976 61S'.7 76-S3013
ISBN-13: 978-1-4613-4153-6 e-ISBN-13:978-1-4613-4151-2
001: 10.1007/978-1-4613-4151-2
Proceedings of an International Symposium on Mass Spectrometry in
Drug Metabolism held at the "Mario Negri" Institute for
Pharmacological Research, June, 1976
© 1977 Plenum Press, New York
Softcover reprint ofthe hardcover 1st edition 1977
A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N. Y. 10011
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Foreword
When a dose of drug is administered, three main phases of
drug action may be distingushed. In the "pharmaceutical" phase
the dosage form disintegrates, the active substance dissolves and
becomes available for absorption. The second phase ("pharmaco
kinetic" phase) includes absorption, distribution, metabolism,
and excretion. That fraction of the dose which finally reaches the
circulation after absorption will be available for biological
action in the third, or "pharmacodynamic" phase when the drug
reaches the target tissues and a drug-receptor interaction takes
place. The objectives in studies of drug metabolism are: (a) to
identify the pathways by which drugs are transformed in the body;
(b) to ascertain quantitatively the importance of each pathway
and intermediate; (c) to identify and quantify endogenous
constituents influenced by the drug or its metabolites which may
interfere with common metabolic processes.
Since metabolites usually differ from their precursors by
only a single chemical group, the resulting metabolic pathways
generally consist of a series of closely related compounds. Mass
spectrometry is uniquely suited for the analysis of drugs and
metabolites for several reasons: only a minimal amount of sample
preparation is needed, closely related compounds can be analyzed
in a single step, structures can often be deduced directly from
the mass spectra without the need for pure reference spectra, and
constituents can be quantified with relative ease even when present
in fractional nanogram quantity. Recent developments in mass
spectrometric and computer instrumentation and analytical techniques
elevated mass spectrometry to a unique status: high sensitivity
and high selectivity are provided simultaneously and are combined
with general applicability to most drugs currently in use.
This volume presents the papers given during a 3-day
international symposium on the use of mass spectrometry in the
study of drug metabolism held in Milan, Italy, in June 1976. Most
papers are contributed scientific papers describing original
research. Several papers were invited reviews covering selected
areas of techniques and applications. Three major areas were
v
FOREWORD
covered: drug metabolism, developments in methodology, and drug
abuse. In the field of drug metabolism, sessions were held on the
identification of metabolites, on quantification studies, and on
the reactivity of intermediates. Special sessions in methodology
development were devoted to new ionization techniques, to the use
of stable isotopes in drug metabolism, and to ancillary instrument
ation such as capillary columns, pyrolyzers and, of course,
computers. The last session was devoted to drug abuse.
The careful selection and mixing of review articles and
original papers should provide the reader both with a comprehensive
picture of the current status of mass spectrometry in drug
metabolism research and a detailed insight into a variety of
applications of current interest.
Thanks to the efforts of Drs. A. Frigerio and E. Ghisalberti,
the organizers of the Symposium, and also the staff of the Mario
Negri Institute, the host for the Symposium, the participants of
this event had a unique chance to meet, listen to, and sometimes
interrogate - in a pleasant and conducive environment - several
leading experts in this field. It was the consensus of those who
attended that mass spectrometry is indeed a uniquely suitable
tool for the study of drug metabolism. We hope that readers of
this text will agree.
John Roboz
Preface
The papers collected in this volume were presented at the
International Symposium on Mass Spectrometry in Drug Metabolism
held at the "Mario Negri" Institute for Pharmacological Research
in June 1976.
One of the primary aims of the Symposium was to bring together
researchers of diverse experience but with some common interests.
It was felt that this would promote critical discussion and a
beneficial exchange of ideas and experiences.
For a symposium to be of value to those who did not participate,
the proceedings should be made available as soon as possible. The
problem confronting the editors was to choose between two possibil
ities: to publish all the papers presented, which might have led
to a significant delay in publication, or to aim for a rapid pub
lication of most of the papers presented. We have chosen the
second alternative, hoping in this way better to serve the interests
of those for whom the book is intended.
The Editors
Milan,
January, 1977
vii
Contents
IDENTIFICATION OF DRUGS AND DRUG METABOLITES
A study on the metabolism of feprazone utilising
mass spectrometry
A. DONETTI, L.G. DRING, P.C. HIROM AND R.T. WILLIAMS... 1
Identification of some urinary metabolites of iopronic
acid in human, rat and dog
D. PITRE, A. FRIGERIO AND R. MAFFEI-FACINO ••.•...•.... 13
Metabolite identification by GC-MS: species differences
in the metabolic patterns of isopropylbiphenyl
H.R. SULLIVAN, R.E. McMAHON, D.G. HOFFMAN AND
S. RIDOLFO............................................. 31
Structural elucidation of an S-oxidized metabolite of
trithiozine in rat and dog
G. PIFFERI, P. VENTURA, C. FARINA AND A. FRIGERIO •.•••. 45
Some metabolites of 9-hydroxy-19,20-bis-~-prostanoic
acid
R. CAPONI, R. FUMAGALLI, S. INNOCENTI, P. MARTELLI
AND U. VALCAVI......................................... 61
Formation of a new amino acid as a metabolic intermediate
of sodium dipropylacetate
I. MATSUMOTO, T. KUHARA, M. YOSHINO AND M. TETSUO ..••.• 73
Identification of the N-acetyl-S-aryloxyalanines from
rats treated with 3-(p-tolyloxy)-1,2-propanediol and
3-phenoxy-l,2-propanediol
T. KUHARA, Y. INOUE AND I. MATSUMOTO .•..•••••..•••••••• 81
Metabolism in rat, dog and man of difenpiramide, a new
anti-inflammatory drug
E. GRASSI, G.L. PASSETTI, A. TREBBI AND A. FRIGERIO •••. 95
ix
x CONTENTS
Potential drugs from propo1is
E.L. GHISALBERTI, P.R. JEFFERIES AND R. LANTERI •.•••••• 111
QUANTITATION OF DRUGS AND DRUG METABOLITES
Mass fragmentography (single and mUltiple ion monitoring)
in drug research
A. FRIGERIO AND E.L. GHISALBERTI ••••••••••••••••••••••• 131
Mass spectrometric identification and quantification of
compounds involved in the metabolism of pyrazofurin
J. ROBOZ AND T. OHN'UMA................................. 151
Mass spectrometry applied to metabolism studies of Org
GC 94, a new anti-migraine drug
J. VINK, J.J. de RIDDER, C.J. TIMMER AND H. de NIJS •••• 167
The identification and measurement in urine of dihydro
digoxin, a cardioinactive metabolite of digoxin
H. GREENWOOD AND W. SNEDDEN............................ 179
Determination of dimethylnitrosamine in extracts from
cultures of Trichomonas vagina1is, using gas
chromatography and mass spectrometry
M. CARAMIA, G. POLl, M. LANDI AND L.F. ZERILLI •.••••••• 191
Blood concentrations of monoacy1cadaverines in
schizophrenia
H. DOLEZALOVA, M. STEPITA-KLAUCO, J. KUCERA,
H. UCHlMURA AND M. HIRANO.............................. 201
MHPG, amitriptyline and depression: a collaborative
study
E. SACCHETTI, E. SME RALD I , E. ALLARIA, M. CAGNASSO
AND P. A. BIONDI........................................ 215
Drugs and drug metabolites as environmental contaminants:
detection of ch1orophenoxyisobutyrate and salicylic acid
by GC-MS
C. HIGNITE AND D.L. AZARNOFF ••••••••••..••••••••••••••• 225
INTERMEDIATES IN THE METABOLISM OF DRUGS
Application of chemical ionization MS and the twin-ion
technique in the analysis of reactive intermediates in
drug metabolism
S.D. NELSON, J.R. MITCHELL, AND L.R. POHL •..•....•.•..• 237
CONTENTS xi
Relationship between structure and metabolism of
tricyclic drugs: stable epoxide-diol pathway
A. FRIGERIO AND C. PANTAROTTO ••.•..••..........•.•...•• 251
STABLE ISOTOPE LABELLING
A study of protein metabolism in chronic-enterocolitis
patients and the effect of pharmacological agents using
mass spectrometry
A.S. BELOUSOV, N.A. BREDIKHINA AND L.T. ZHURAVLEV ••••.. 277
Biochemical applications of high precision isotope
analysis by combined gas chromatography-mass spectrometry
E.J. HERON, E.J. BONELLI AND C.T. GREGG .•.•.•.........• 285
DEVELOPMENTS IN METHODOLOGY
Chemical ionization mass spectrometry in the
identification of drugs and drug metabolites
E.L. GHISALBERTI •••......•..........•..•..•..•..•...... 291
Field desorption mass spectrometry of pharmacologically
active salts
W.D. LEHMANN AND H. -R. SCHULTEN ....................... 325
Role of computers in gas chromatography-mass spectrometry:
detection, identification, and quantification in drug
metabolism research
J. ROBOZ............................................... 343
A real time gas chromatograph-mass spectrometer mini
computer system for selected ion analysis
J.A. STEINBORN, R.W. SILVERMAN AND D.J. JENDEN ...•.•..• 365
DRUG ABUSE
Can gas chromatography - mass spectrometry influence
trends in drugs abuse?
H. BRANDENBERGER....................................... 379
Characterization of in vivo liver metabolites of ~l_
-tetrahydrocannabino~by EI and CI mass spectrometry
D.J. HARVEY, B.R. MARTIN AND W.D. PATON •.......••...••. 403
xii CONTENTS
Detection and quantification of cannabinoids in human
blood plasma
A. OHLSSON, J.-E. LINDGREN, K. LEANDER, S. AGURELL ••••• 429
Identification of a major metabolite of tetrahydro
cannabinol in plasma and urine from cannabis smokers
M. NORDQVIST, J.-E. LINDGREN AND S. AGURELL ••••.••••••• 441
Analysis of impurities in illicit heroin by mass
spectrometry
M. KLEIN .......................•...•................... 449
Screening by gas chromatography-mass spectrometry for
metabolites of five commonly used anabolic steroid drugs
R.J. WARD, A.M. LAWSON AND C.H.L. SHACKLETON ••..••••••• 465
Mass spectrometry in acute intoxication diagnostics:
aspects and experiences
G. BRANTE, S. JONSSON AND A. ANDERSSON ••.••••..•••••••• 475
PARTICIPANTS •••.••••.••.•••.••..•.••••..•........••....•• 503
INDEX ••..•..•••.••..••..•..••.....•.••.••.••••.....••...• 509