Pharmacokinetics: Mathematical and Statistical Approaches to Metabolism and Distribution of Chemicals and Drugs

348 Pages·1988·8.1 MB·English

by  Erich Gladtke (auth.), A. Pecile, A. Rescigno (eds.)

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,
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The senes IS published by an International board ot publishers In conJunctlon wlth the
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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,