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348 Pages·1988·8.1 MB·English
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Pharmacokinetics Mathematical and Statistical Approaches to Metabolism and Distribution of Chemieals and Drugs NATO ASI Series Advanced Science Institutes Series AsefIes presenting the results of activities sponsored by the NA TO SClence Commlttee, which alms at the dlssemmatlon of advanced sClentific and techn%glca/ know/edge, wlth a Vlew to strengthening /mks between sClentiflc communities The senes IS published by an International board ot publishers In conJunctlon wlth the NATO Scientitic Attalrs DIvIsion A Life Sciences Plenum Publishing Corporation B Physics New York and London C Mathematical D. Reidel Publishing Company and Physical Seien ces Dordrecht, Boston, and Lancaster o Behavioral and Social Seien ces Martinus Nijhoff Publishers E Engineering and The Hague, Boston, Dordrecht, and Lancaster Materials Seien ces Springer·Verlag F Computer and Systems Sciences Berlin, Heidelberg, New York, Londqn, G Ecological Seien ces Paris, and Tokyo H Cell Biology Recent Volumes in this Series Vo/ume 138-Chaos in Biological Systems edited by H. Degn, A. V. Holden, and L F. Olsen Vo/ume 139-Lipid Mediators in the Immunology of Shock edited by M. Paubert·Braquet Vo/ume 140-Plant Molecular Biology edited by Diter von Wettstein and Nam·Hai Chua Vo/ume 141-Nervous Systems in Invertebrates edited by M. A. Ali Vo/ume 142-A Multidisciplinary Approach to Myelin Diseases edited by G. Serlupi Crescenzi Vo/ume 143-Antiviral Drug Development: A Multidisciplinary Approach edited by Erik Oe Clercq and Richard T. Walker Vo/ume 144-H·2 Antigens: Genes, Molecules, Function edited by Chella S. David Vo/ume 145-Pharmacokinetics: Mathematical and Statistical Approaches to Metabolism and Distribution of Chemicals and Drugs edited by A. Pecile and A. Rescigno Series A: Life Sciences Pharmacoki netics Mathematical and Statistical Approaches to Metabolism and Distribution of Chemicals and Drugs Edited by A. Pecile University of Milan Milan, Italy and A. Rescigno University of Ancona Ancona, Italy Springer Science+Business Media, LLC Proceedings of a NATO Advanced Study Institute on Pharmacokinetics, held June 2-13, 1987, in Erice, Italy Library of Congress Cataloging in Publication Data NATO Advanced Study Institute on Pharmacokinetics (1987: Erice, Italy) Pharmacokinetics: mathematical and statistical approaches to metabolism and distribution of chemicals and drugs. (NATO ASI series. Series A, Life sciences; v. 145) "Proceedings of a NATO Advanced Study Institute on Pharmacokinetics, held June 2-13, 1987, in Erice, Italy"-T.p. verso. "Published in cooperation with NATO Scientific Affairs Division." Includes bibliographies and indexes. 1. Pharmacokinetics-Mathematical models-Congresses. 2. Pharmacokine· tics-Statistical methods-Congresses. 1. Pecile, A. (Antonio) II. Rescigno, Aldo. III. North Atlantic Treaty Organization. Scientific Affairs Division. IV. Title. V. Series. [DNLM: 1. Drugs-Pharmacokinetics-congresses. 2. Mathematics- congresses. 3. Tissue Distribution-congresses. QV 38 N2785p 1987] RM301.5.N37 1987 615.7 87-36043 ISBN 978-1-4684-5465-9 ISBN 978-1-4684-5463-5 (eBook) DOI 10.1007/978-1-4684-5463-5 © 1988 Springer Science+Business Media New York Originally Published by Plenum Publishing Corporation in 1988 Softcover reprint of the hardcover 1s t edition 1988 AII 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 DIRECTORS A, PEC I lE, HEAD OF THE DEPT, OF PHARMACOLOGY, CHEMOTHERAPY AND MEDICAL TOXICOLOGY, UNIVERSITY OF MILAN, ITALY A, RESCIGNO, PROFESSOR OF PHARMACOKINETICS, INSTITUTE OF EXPER, AND CLINICAL MEDICINE, UNIVERSITY OF ANCONA, ITALY ORGANIZING COMMITTEE A, PECIlE, PROFESSOR OF PHARMACOLOGY, UNIVERSITY OF MILAN, ITALY A, RESCIGNO, PROFESSOR OF PHARMACOKINETICS, UNIVERSITY OF ANCONA, I TAL Y J,H, MATIS, PROFESSOR OF STATISTICS, TEXAS A&M UNIVERSITY, COLLEGE STATION, TX, U,S,A, A,K, THAKUR, PH,D" PRINCIPAL SCIENTIST & BIOSTATISTICIAN, HAZLETON LABORATORIES AMERICA, INC" VIENNA, VA, U,S,A, SECRETARY MARIA lUISA PECIlE, INTERNATIONAL CONGRESSES & COURSES SECRETARIAT, DEPARTMENT OF PHARMACOLOGY, CHEMOTHERAPY AND MEDICAL TOXICOLOGY, UNIVERSITY OF MILAN, ITALY v PREFACE Pharmacologists can be considered pioneers of the study of kinetics of materials introduced into biological systems. The study of drug kinetics is particularly suited to a formulation of relatively simple models which make possible an interpretation of the time-dependent nature of various important phenomena (e.g. distribution by means of diffu- sion through membranesl. The objective of the NATO ASI Course on Pharmacokinetics was that of presenting and dis- cussing the mathematical and statistical approaches current- ly available or being developed for the description, inter- pretation and prediction of the fate of drugs and tracer substances administered to living beings. Different physi- cal methods for measuring drugs and tracer substances were considered, but the emphasis was on the interpretation of the results of the measurements in terms of mathematical and statistical models. The present book contains all invit- ed lectures given in this Course by outstanding internation- al authorities and specialists from different fields. A great effort was made to keep a balance among the mathemati- cal, physical, biological and clinical aspects of the prob- lems; exchange of ideas and experiences between scientists with a physico-mathematical background and scientists with a biomedical background was encouraged and all participants were deeply involved in fruitful discussions. This unique feature of the Course is also the unique characteristic of this book which is therefore mainly directed to people interested not just in acquiring a working knowledge of the methods but in developing new methods. Thus we hope this book will be judged as achallenging presentation of new trends for future developments in Pharmacokinetics rather than a review of today's knowledge. We take this opportunity to thank the NATO Scientific Affairs Committee for its support. The contribution of the Centro Nazionale delle Ricerche (C.N.R.l of Italy is kindly acknowledged. Warm thanks are also due to Bracco Industria Chimica S.p.A. and Istituto Oe Angeli S.p.A. for their generous financial assistance. vii We wish to thank each of the lecturers and ASI partici- pants for their effort in making the Course a success: the interaction of scientists from research institutions with people actually involved in the production and testing of drugs has proven particularly fruitful for both Industry and University. We thank the International School of Pharmacology for hous- ing the Course at the "Ettore Majorana Centre for Scien- t i f i c Cu 1 t ure" i n E r i ce, a d mir a b 1 y dir e c ted. T h e i mp 0 r t a n t organisational work done by Dr. Maria Luisa Pecile was highly appreciated. A. Pecile, A. Rescigno viii CONTENTS History of Pharmacokinetics .................... . E. Gladtke Conceptual Foundations and Uses of Models in Pharmacokinetics ...................... . 11 J.S. Beck Development of Compartmental Concepts .......... . 19 A. Rescigno and A.K. Thakur Modeling of Pharmacokinetic Data ............... . 27 A.K. Thakur Mathematical Foundations of Linear Kinetics ..... 61 A. Rescigno An Introduction to Stochastic Compartmental Models in Pharmacokinetics ............... . 113 J.H. Matis Modeling First-Pass Metabolism ................. . 129 J.G. Wagner Saturable Drug Uptake by the Liver: Models, Experiments and Methodology .............. . 1 51 L. Bass Physiological Models, Allometry, Neoteny, Space-Time and Pharmacokinetics .......... . 1 91 H. Boxenbaum and R. D'Souza Equivalence of Bioavailability and Efficacy in Drug Testing .......................... . 21 5 C.M. Metzler Modeling and Risk Assessment of Carcinogenic Dose-Response ............................ . 227 A.K.Thakur ix The Puzzle of Rates of Cellular Uptake of Protei n-Bound Ligands .................... . 245 L.Bass and S.M. Pond A Pharmaeokinetie Equation Guide for Clinieians ..................... . 271 J. Mordenti Pharmaeokinetie Studies in Man ................. . 291 J.G. Wagner Metabolie Models in Radiation Proteetion ....... . 323 F. Breuer Author Index ................................... . 337 Subjeet Index .................................. . 339 x HISTORY OF PHARMACOKINETICS Erich Gladtke Director of the hospital for sick children of the university of Cologne 0-5000 Cologne 41 INTRODUCTION By pharmacokinetics we mean the science of the quantitative actions between a biological organism and a pharmacological substance within it. The qualitative question of the actions exerted by a drug does not con- stitute part of the primary concern of pharmacokinetics, it belongs to pharmacology as a whole. The word "pharmacokinetics" first appeared in print on page 244 of the first comprehensi ve treatise of pharmacokinetics, F. H. Dost' s book "Der Blutspiegel" ("Blood Levels") (9); this was the point at which the term and the concept became part of the scientific vocabulary. Dost himself, when taking part in a small discussion group in 1966, asked about the or- igin and the first use of the term, and was astonished when Ekkehard Krü- ger-Thiemer promptly gave him this answer. F.H. Dost was born 11th July 1910 in Dresden. He received his educa- tion in medicine and pharmacology at different places in Germany and be- came pediatrician at the Childrens hospital of the University of Leipzig. From 1947 to 1951 he hold the position as lecturer and head physician at Leipzig, 1951 to 1960 as professor and director of the famous childrens hospital of the Charite in Berlin, and from 1960 to 1975 he held the same position at Giessen. The "Blutspiegel" appeared in 1953, in 1949 the first paper of this topic was published by Dost (8). There had, i t is true, been forerunners who had not only measured blood concentration curves but had also derived the same or similar for- mulae and laws to those later gathered together and summarized by Dost; but these workers had generally only applied their knowledge to the solu- tion of one or two problems, and had not come anywhere near formulating general rules. To my mind, the classic example of the application of what was actu- ally a general law to the solution of just one single problem was Wid- mark's analysis of curves of blood ethanol and acetone concentrations. Widmark's famous work on blood alcohol is often considered to be one of the very first papers on pharmacokinetics. This monograph appeared in 1932 (26) and is important in our context, because Widmark here tries to relate blood levels of alcohol to psychic impairment. This work, however,

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