Biopharmaceutics

and Clinical
Pharmacokinetics
Biopharmaceutics
and Clinical
Pharmacokinetics
AN INTRODUCTION
Fourth Edition, Revised and Expanded

Robert E. Notari
College of Pharmacy
The Ohio State University
Columbus, Ohio

0 CRC Press
Taylor & Francis Group
Boca Raton London New York

CRC Press is an imprint of the

Taylor & Francis Group, an informa business
Publisher’s Note

The publisher has gone to great lengths to ensure the quality of this book
but points out that some imperfections from the original may be apparent.
To my parents
Contents

Preface to the Fourth Edition vii

Preface to the Third Edition xi
Preface to the Second Edition xiii
Preface to the First Edition XV
Nomenclature xix

l. Introduction
References 4

2. Rates, Rate Constants, and Order 6

I. Order 6
II. Rates and Rate Constants 7

3. Active and Passive Transport 22

I. Introduction 22
II. Passive Transport 23
II I. Active Transport 37
References 44

4. Pharmacokinetics 45
I. Introduction 47
II. Drug Disposition 48
II I. Constant-Rate Intravenous Infusion 89
IV. Compartmental Models and Their Limitations 106
V. Absorption Rate Constants 117
References 128

v
vi Contents

5. Biopharmaceutics 130
I. Extravascular Administration 132
II. Absorption of Drugs from the Gastrointestinal Tract 134
III. Factors Influencing Bioavailability 160
IV. Evaluation of the Bioavailability of a Single Drug 171
V. Drug Delivery to Prolong Duration 191
References 218

6. Dosage Regimens 221

I. Introduction 222
II. Accumulation During Repetitive Dosing 224
III. Adjustment of Dosage Regimen in Renal Failure 255
IV. Multiple Dosing of Constant-Rate Intravenous Infusions 267
References 271

7. Pharmacokinetic Aspects of Structural Modifications in

Drug Design and Therapy 273
I. Introduction 275
II. Antimicrobial Agents 288
II I. Pharmacokinetics of Prod rugs 316
IV. Stereoisomers 338
References 341

8. Pharmacokinetic Applications in Clinical Practice 349

I. Introduction 351
II. Pharmacokinetic Drug Interactions 354
III. Clinical Pharmacokim:tics 369
References 400

Appendix 405

Index 407
Preface to the Fourth Edition

Biopharmaceutics and pharmacokinetics are quantitative subjects. One can-

not appreciate their meaning simply by reading about them any more than
one could learn mathematics by reading descriptions of it. This text is designed
to help the reader to discover their meaning through experience in the manner
that a researcher would gain such insight. The experience is provided by
analyzing data presented in problems. These problems are strategically placed
to complement the descriptions of each concept, thus making this text a
workbook. The format can best be regarded as a complete course, wherein
the subjects are presented in sequence. The student is expected to interact
by solving problems, but may, depending upon the level of past experiences,
omit material. Based on this text a typical course outline might be:

I. Introduction and Overview

II. Kinetic Analysis of Data: Order and Rate Constants
III. Kinetics of Drug Transport Through Membranes
IV. Model-Independent versus Compartmental Model Pharmacoki-
netic Analyses
V. Biopharmaceutics in the Evaluation and Design of Drug Delivery
Systems
VI. Dosage Regimen Design and Adjustment in Renal Failure
VI I. Pharmacokinetic Evaluation and Design in Molecular Modification
VIII. Application of Pharmacokinetics to Drug Therapy

Presentation of these subjects is meant to form a logical chain. Chapter I

gives an historical perspective, emphasizing the half-century lag period between
the awareness of drug product quality and the concern for bioavailability.
The kinetic analysis of data comprises Chapter 2, which teaches how to plot
viii Preface to the Fourth Edition

data to treat first-order, zero-order, or Michaelis-Menten kinetics. Drug

transport is addressed in Chapter 3, which extends kinetic analyses to active
and passive transport, the influence of protein binding and pH, and data
treatment involving asymptotic values. The calculation of pharmacokinetic
parameters bas~d on model-independent analyses is presented in Chapter 4.
Because of widespread use of modeling in the literature, one-, two-, and
three-compartment open-model methods, together with their limitations, are
also presented. Biopharmaceutics is treated in Chapter 5, which stresses how
the formulation can influence the drug plasma concentration time-course. It
includes factors influencing absorption, clinical assessment of bioavailability,
design of controlled-release devices, and clinical evaluations. Since these
subjects entail analyses of drug plasma concentration time-courses, bio-
pharmaceutics is intentionally placed after the pharmacokinetic chapter,
which deals with the fate of a drug introduced into the blood. Dosage reg-
imens are covered in Chapter 6, which presents the kinetic determination of
size and frequency of dosing to achieve desired clinical endpoints, together
with methods for individualizing regimens in disease states such as renal
failure. The evaluation of molecular effects on pharmacokinetics is a unique
aspect of this text. Chapter 7 discusses how the structure can influence the
time-course of drug in the blooct in contrast to the influence of the formu-
lation. It is aimed at casting aside many common misconceptions regarding
comparisons of pharmacokinetic data for prodrugs and closely related ana-
logs; several classes of antibiotics are reviewed to illustrate these effects.
Finally, Chapter 8 addresses how the patient can influence the pharmaco-
kinetic behaviorofthedrugandwhatcompensatory measures are appropriate.
It begins with a survey of factors which may alter drug pharmacokinetics
beyond what is therapeutically acceptable. The monitoring of drug plasma
levels and dosage adjustmento; of five agents are then reviewed as examples
wherein risk dictates individualization. The level of expertise gained by
completing this sequ"ence should allow the reader to understand the literature
and to enter a higher-level course with a thorough appreciation for the
significance of the subjects.
One of the primary changes made in this edition is the stress on model-
independent pharmacokinetics. A section on classical pharmacokinetic mod-
eling is included for completem:ss, but its limitations are also emphasized.
In keeping with this goal, the symbols published by the Committee for
Pharmacokinetic Nomenclature of the American College of Clinical Phar-
macology (1982) have been adopted (see the Appendix, p. 405). This system
allows a single model-independent definition for terms which otherwise require
separate symbols for each model. For a more detailed explanation, see
Nomenclature (p. xix). Other notable changes include an increased number
of problems, an expanded treatment of bioavailability, and a reduction in
Preface to the Fourth Edition ix

the fundamentals of those kinetics which precede pharmacokinetics, so that

the reader's preparatory time to reach the title subject is minimized. Log-
arithmic tables are deleted from this edition as it is assumed that pocket
calculators have made them obsolete. The reader will find a calculator that
will handle exponentials to base e is convenient in the dosage regimen
calculations.
Any criticisms, suggestions, or questions would be most gratefully received
by the author.

Ro6trt E. NottJri
Preface to the Third Edition

The first edition, written during the 1960s and published in 1971, noted that
"The approaches discussed here may seem a bit too sophisticated and costly
to the reader who has not previously come upon the concept of an indivi-
dualized dosage regimen." This statement followed a discussion suggesting
that "pharmacokinetics will make an ever increasing contribution to the
rational clinical use of drugs ..." The second edition ( 1975) contained "a
new addition covering dosage regimen calculations in patients with normal
renal function or with renal failure," together with an additional chapter on
the pharmacokinetic aspects of molecular modification. The latter was
described as "a field which is relatively undeveloped." These applications
of pharmacokinetics were minor components in the second edition and absent
from the first edition.
The immense progress in these two areas, clinical pharmacokinetics and
pharmacokinetic drug design, has necessitated the writing of this third edi-
tion. They now occupy roughly one-half of this text. Chapters 5 and 7 are
devoted to clinical pharmacokinetics. The application of pharmacokinetics
to drug design and evaluation comprises Chapter 6, the longest in the text.
Progress in the development of prodrugs represents a major portion of this
expanded chapter.
I must reemphasize that the text is not intended as a review but rather
an introduction. Development of concepts is the primary goal, and examples
have been selected to illustrate them. Problem solving by the reader remains
the rrwdus operandi for comprehending the principles and their applications.
As in previous editions, it is the author's hope that this text will provide a
starting place for those who wish to pursue further study or who want only
a simplified but quantitative appreciation of the field.
The many inquiries I have received over the years have proven invaluable
in identifying areas for revision. I am most grateful to all those who have

xi
xii Preface to the Third Edition

graciously given helpful comment or asked for clarification; both provide

insight that an author cannot attain for himself. I particularly wish to
acknowledge Dr. Adam Danek, Dr.Jacek Bojarski, and Dr. Halina Kra-
sowska, who stimulated the publi<:ation of the second edition in Poland ( 1978)
and who translated the English edition into Polish. This experience provided
great encouragement to me, and the questions surrounding the translation
called attention to several ambiguities that have led to rewording in the third
edition. The continued beautiful art work of Yvonne Holsinger and the
excellent typing of Sue Sheffidd are most sincerely appreciated.
I would be grateful to receiv(: any comments or questions from readers
of the third edition as I truly regard both as a service to the author.

Robert E. Notari
Preface to the Second Edition

The objectives of this book are identical to those of the first edition. It is a
place to begin your studies-an introduction. Hopefully, it is both simple
and accurate. And the agreement between reader and author has also remained
constant. This is a workbook. If you are willing to work the problems, the
principles should become meaningful to you by the process of discovery.
To that end the second edition has been modified to make it more self-
sufficient. As each new principle is introduced, two types of problems are
presented. Sample problems are completely solved so that you can diagnose
your error when your answer is not correct (and assuming that mine is!).
Practice problems are designed to test your ability to apply what you have
learned. They are generally slightly more difficult.
The constancy of objectives is not a reflection of a lack of progress in the
field or a lack of change between the editions. Indeed, the second edition is
largely a new book. In accomplishing the updating and improving of the
book, the author gratefully acknowledges the indispensable contributions of
co-authors joyce L. DeYoung (Chapters 2 and 3) and Raymond C. Anderson
(Chapter 5).
Those who are familiar with the first edition will find it helpful to know
what changes have been made. Chapter 2 and 3 have been completely rewrit-
ten and restyled. While they cover the same subject matter, the order of
presentation is different. Chapter 2 now contains pharmacokinetic models
and the basic kinetics required to understand them. For example, a beaker
is still used to teach two-compartment model kinetics, but it is immediately
followed by the analogous situation in pharmacokinetics. The basic kinetics
are therefore kept minimal and limited to models with pharmacokinetic
counterparts. Chapter 3 contains methods and discussions for calculating
pharmacokinetic parameters. Among the notable changes is the expansion
of the section dealing with the apparent volume of distribution. This has

xiii
xiv Preface to the Second Edition

been completely updated to include both discussion and equations regarding

variation in calculated values obtained by different methods for multicom-
partmental drugs.
Chapter 4 has been expanded. It begins with a revised section on the
interpretation of blood level curves and ends with a new addition covering
dosage regimen calculations in patients with normal renal function or with
renal failure. This latter area is one of the most widely recognized contri-
butions of pharmacokinetic sciem:es to improved clinical therapy.
Chapter 5 is a new addition to the book. It is aimed at fostering both an
understanding and an interest in the effects of molecular manipulation on
pharmacokinetic parameters and the resultant pharmacologic impact. This
is a field which is relatively unde\·eloped (as compared with studies on dosage-
form effects) but which will be a key to future evaluation and development
of new drugs.
The second edition is amply rc:ferenced. Each chapter provides sufficient
citations for the interested reader to check on the validity or limitations of
the subject matter presented or to become more familiar with a particular
field.
Again, I would greatly appredate receiving comments, criticisms, sug-
gestions, opinions, or notifications of errors regarding any section of the
book. A similar invitation in the preface to the first edition was accepted by
several people, whose comments had a direct influence on the production of
the second edition. While I canr..ot cite them all, I would particularly like
to thank Dr. Adam Danek, Dr. G~rald E. Schumacher, Dr. Donald A. Zuck,
and Dr. James W. Ayres for th<:ir helpful suggestions, encouraging com-
ments, and poignant questions.

Robert E. Notari
Preface to the First Edition

This book is designed as an introductory text for use in formal courses or

for self-study. It is aimed at both biomedical researchers and practitioners.
The book assumes no prior knowledge of either kinetics or calculus on the
part of the reader. Derivations are provided for those who are mathematically
inclined. Those who are not may simply make usc of the final or "working"
equations. None of the subjects is beyond the level of comprehension of an
advanced undergraduate with no calculus background. However, one must
approach this book "actively," with graph paper and pencil in hand and
with desire to learn well in mind. The material is presented in "building-
block" fashion, and it is imperative that the user solve the examples and
practice problems to have all of the pieces necessary to build a solid foun-
dation. Topics are covered in a cumulative manner, and skipping a principle
will almost certainly result in an inability to understand a subsequent topic
fully. Although it is not a programmed text, it must be approached in the
same fashion-as a workbook. Casual reading will not suffice.
One problem that faces those who develop an interest in learning bio-
pharmaceutics and pharmacokinetics for the first time is how to get started.
Byron once wrote, "Nothing is more difficult than a beginning." This is
certainly true for the present subject. Most current references are not written
at the basic introductory level. They assume that the reader has some level
of sophistication in either calculus or kinetics or both. In addition they do
not provide for active participation in the form of problem solving. A teacher
wishing to develop a course would have to do so from the literature. Yet it
is difficult to read the literature without a fundamental knowledge of the
field. This book is meant to provide that knowledge for teachers, students,
biomedical practitioners, and research scientists in medicinal chemistry,
pharmacology, pharmacy, and other biomedical disciplines. Chapters 2 and
3 comprise the basic introductory materials, and Chapter 4 illustrates some

XV
xvi Preface to the First Edition

of the applications. An understanding of this text should provide sufficient

introduction to the field to allow further reading of more complex applications
in the literature
During the past six years I have been teaching biopharmaceutics to senior
students in the College of Phannacy of The Ohio State University. The
absence of a textbook for the course has presented a number of difficulties.
Although assigned readings of review articles and selected chapters have
proven helpful, they fail to provide the structural foundation that a textbook
achieves. Students repeatedly failed to visualize the total structure of the
subject material until the course was nearly complete in spite of the fact that
detailed syllabi and other outlim:s were distributed each quarter. Students
were generally accustomed to working with a required text which serves to
define the course goals in much more detail and provides a means for reading
ahead. Furthermore, when a stud•:nt experienced difficulties in solving home·
work problems, there was no reference book to provide additional information
over and above that found in the lc:cture notes. Problem sets had to be created,
printed, and distributed in lieu of an available source such as a required
text. There was no provision for a.dditional practice problems for the student
who felt the need for such experience.
As a result, the outlines, problem sets, graphic demonstrations, classroom
handouts, short presentations of principles, etc., grew in both number and
in size until some of the materials distributed to the class approached the
size of a chapter or even a small book. Most of the contents of this text have
evolved from the development of these undergraduate teaching aids. Some
of the subject matter was add<:d later to accommodate an intermediate level
graduate cours<:. All of the examples and practice problems have been worked
many times over by undergraduate and graduate students alike. Over the
past two years (and prior to its publication) the book has been successfully
used as a required text in both undergraduate and graduate courses here at
Ohio State.
It would be impossible to list the names of all those students whose
comments and general intereM !erved to stimulate the writing of this book
as well as to influence its contents and mode of presentation. Certainly I
must acknowledge the graduating classes of the College of Pharmacy of The
Ohio State University from 196~' through 1971, who had the dubious honor
of serving as "guinea pigs" for the development of this course. Sincere thanks
for their patience and enthusiasm. It is with pleasure that I thank the grad-
uate students and faculty who re.:td the text and in some cases helped develop
the problems and examples. Among them I wish especially to acknowledge
the efforts of Miss Marilyn Lue Chin, Mrs. Joyce De Young, lmtiaz Chaudry,
Raymond Anderson, and Dr. Rkhard H. Reuning. The physical appearance
Preface to the First Edition xvii

of the text is a testimonial to the fine art work of Mrs. Yvonne Holsinger
and the excellent typing of Miss CarolJ. Lusk.
Finally, any comments, criticisms, suggestions, errors or improvements
would be most gratefully received by the author.

Robtrl E. Notari
Nomenclature

Those who are familiar with the nomenclature system involving A, a, B, P

may find it helpful to examine its relationship to the system used herein [1].
For a complete listing of symbols and their definitions, please see the Appen-
dix (p. 405). It is a simple system wherein each exponential multiplier is
given the same symbol,~. subscripted sequentially until the final entry, which
is always given the subscript z, i.e., ~z. Thus, the counterparts to the older
systems are given by the following, where C is concentration in plasma
following intravenous administration:

mJJnJJtxponential
C = Cot-1<1
C = C(O)t-~zl
hitxpontntiai
C = Ae-a1 + Be-l!'
C = C1t-~,,+ Cze-~7. 1

tritxponential
C = At-"' + Be-!!' + Gt_..,,
C = C1t-"•' + c~-~.; + Czt-"z'

A model-independent definition for biological half-life is thus t 1n = 0.693/

~z, which fits the mono-, bi-, and triexponential situation without having to
rewrite the equation in terms of K, p, and-y. Similarly, clearance may be
defined as CL = ~zVz, where V2 is defined as (DOSE)/(AUC)(~z). Both of
these are model-independent definitions which apply to all three cases.
The remainder of the nomenclature is sufficiently similar to popularly
employed systems to require no explanation. The primary change lies in the
use of A and the apparent volume of distribution, V2 . These are based on

xix
XX Nomenclature

sufficient logic to make them easily acceptable on usage especially since they
afford such convenience in making model-independent definitions.

REFERENCE

I. Manual of Symbols, EquaJiDns a.'ld Definitions in Phamuuokirutics, Committee

for Pharmacokinetic Nomenclature, American College of Clinical Phar-
macology, Philadelphia, Pennsylvania, 1982.
Biopharmaceutics
and Clinical
Pharmacokinetics
1
Introduction

It is both an enlightening and astonishing experience to read the labels on

so-called cure-ails and tonics on display in museums and occasionally found
collecting dust in remote corners of storerooms in old established pharmacies.
Since we are no longer obliged to take these medicines when we become ill,
we may even see a great deal of humor in their claims. Therapeutic effec-
tiveness was generally certified on the basis of testimonials or anecdotal
evidence. Modesty was not a characteristic of promotional statements. Ham-
lin's Wizard Oil, "The Great Medical Wonder," recognized no limitations in
stating, "There is no sore it will not heal. No pain it will not subdue." Dr.
King's New Discovery was favorably compared with other recent inventions
such as the steamship, steam engine, automobile, telephone, telegraph, and
radio. According to the advertisement, it rated well as "The Greatest of All."
"No-To-Bac made a man of me," another advertisement read, and, picturing
a young man embracing a young woman, it noted that by use of this product
he had "thrown away his pipe and tobacco and thereby won the love of this
stunning girl." A delightful review of that era can be found in the book One
for a Man, Two for a Horse [I]. That title in itself shows that individualization
of dosage regimens (discussed in Chap. 6 of this text) is not as innovative
as one might think. As a final example of immodest claims and an unbe-
lievable dosage regimen, consider the statement regarding Pond's Extract and
made by the popular fictional character Buster Brown: "From my own per-
sonal experiences, Pond's Extract is the best remedy for all inflammations,
hemorrhages, sprains, cuts, bruises, chill blains, burns, scalds, frostbite." So
much for the indications. Now for the clinical results: "It has made a better
ar.d healthier boy of me and is my best friend." And finally the dosage
regimen: "Used externally, internally, and etnnali:J."
How well did the products and claims of yesteryear measure up to the
standards of today? One might use the following criteria:
2 1. Introduction

l. Contents
2. Percent strength
3. Purity
4. Safety
5. Clinical effectiveness
6. Bioavailability

Not only did the contents of such products not appear on the label, but
it is unlikely that the manufacturl!r knew the ingredients. If the contents are
not known, the question of perc:ent strength becomes meaningless. Plant
sources sold for the production of drug products were often adulterated. Even
if the plants used were pure, the active ingredients, if there were any, were
not known. Chemical analyses w-~re neither possible nor of great concern to
a naive society. Some awareness of the danger in such a system probably
evolved as a direct result of unfortunate experiences with products that not
only failed to cure but also caused toxic effects which may have been worse
than the malady. Initially, society responded with legislation aimed at ensur-
ing that medicines were safe and free from adulterants. No doubt these
seemingly simple goals presented tremendous problems, without adding con-
cern for therapeutic effectiveness, which was generally certified on the basis
of testimonials or anecdotal evidence.
The development of analytical chemistry brought about an acute awareness
of the importance of controlling the contents of a product. That each drug
should have an adequate purity rubric became the concern of those given
the responsibility for setting standards for the protection of society. Tests
for physical characteristics wer( introduced, and as analytical technology
advanced, the sophistication of product tests increased. Trace analysis made
limitations on allowable contamination practical. Chemical content and
product purity advanced to a sdentific level commensurate with the ana-
lytical technology of the day.
And so we can observe that since the turn of the century, product devel-
opment has evolved from cure-all herb teas to stable, pure formations con-
taining known amounts of chemicals that have been defined as drugs. It was
quite natural that the scientific community and society at large had confi-
dence in a product which adhered to its purity rubric. This philosophy
dominated from 1938 (when the final drug safety amendments to the Federal
Food, Drug, and Cosmetic Act were made) until relatively recent years.
During that time it was widely assumed that all products containing equal
doses of the same drug were equipotent when put to use by the clinician.
The first four criteria in our list were regarded as sufficient. More recently
we have come to the sometimes surprising realization that percentage chemical
Introduction 3

strength is not the sole criterion for clinical effectiveness. In fact, formulations
were produced and marketed that satisfied all of the required legal standards
but which were not therapeutically active. It became obvious that a dosage
form must not only contain the correct amount of the labeled drug but must
also release that drug upon administration to the patient. Clinical tffictivmess
and hioavailahility were thus added to the criteria for effective drug product
development. A drug should be not only safe but beneficial as well, and its
therapeutic claims must be based upon sound clinical evidence. Furthermore,
a drug which has been proven effective can be rendered ineffective owing to
lack of bioavailability.
What is bioavailability? The simplest concept to consider is that of a
hioavailahle dose. This is the dose available to the patient, in contrast to the
dose stated on the label. Only a drug that is completely absorbed into the
bloodstream will have a bioavailable dose equal to that stated on the label.
In the case of tablets or capsules administered orally, the bioavailable dose
will generally be less than the administered dose. Bioavailability therefore
deals with the transfer of drug from the site of administration into the body
itself as evidenced by its appearance in the general circulation. Since a
transfer process is involved, it may be characterized by both the rate of
transfer and the total amount transferred. The bioavailable dose refers only
to the total amount transferred. A complete description of the bioavailability
of a drug from a dosage form must include both the rate and the amount.
Methods for such characterizations are discussed in this book. Bioavailability
has been defined in various ways [2-5). Those which ignore the rate of
transfer [2,3] are inadequate to explain cases where products show differences
in blood levels and/or clinical response due in total or in part to the rate of
release of drug. A more acceptable definition for hioavailahility is therefore
[5) "a term used to indicate the rate and relative amount of the administered
drug which reaches the general circulation intact."
The measure of success in the use of any drug is the degree to which the
results obtained agree with those expected. Therefore the degree of success
achieved by the use of a drug product may be altered by factors which affect
bioavailability, such as certain foods, other drugs, the dosage regimen, the
route of administration, a less than optimum formulation, or the inappro-
priate use of a suitable formulation. Biopharmaceutics deals with such prob-
lems. It is concerned with obtaining the expected therapeutic effect from a
drug product when it is in use by the patient. One such definition has been
offered as follows [5): "Bioplw.muu:eutics is the study of the factors influencing
the bioavailability of a drug in man and animals and the use of this infor-
mation to optimize pharmacologic or therapeutic activity of drug products
in clinical application."
Since studies involving the rates of drug transfer employ kinetic methods,
biopharmaceutics is closely linked to pharmacokinetics. Indeed, the terms
4 1. Introduction

have been interchanged often in the literature. In this book the following
definition [5] will be used: "Pit.amuu:olcinetics is the study of the kinetics of
absorption, distribution, metabolism, and excretion of drugs and their p,har-
macologic, therapeutic, or toxic response in animals and man."
Finally, consider the term biOftJiliVGleru:y. Like the others, it has been defined
in various ways. We shall use the Jimplest interpretation. Two drug products
containing equal doses of a drug will be said to be bioequivalent if they do
not differ significantly in either their bioavailable dose or its rate of supply.
Thus the time <::ourse for drug in the blood following the administration of
either product would be identic:al. Bioequivalency therefore includes not only
the amount of active ingredient available but also the rate at which it is
available.
A corollary to the more recent concerns for product quality and effec-
tiveness is the challenge to physicians and pharmacists to consider the impact
of these sciences on clinical practice. For example, the clinician must be
informed when the coadministration of other drugs or foods may influence
the bioavailability of an active ingredient. As research defines the critical
factors influencing the absorption of drugs, the information must be put to
clinical use so that practitioners are aware of those situations that should
be avoided.
This concept can be further extended into all areas of biomedical drug
research. Let us consider pharmacology as a case in point. In a broader
sense the concept of bioavailability cannot be circumvented by the choice
of the route of administration. Regardless of where the experiment begins,
the final observations are a funct.ion of the bioavailability of the drug to the
site of action, and the factors influencing its arrival there are many. Since
the movement of drug from the site of administration to the site of action
requires time, the overall process may best be analyzed by pharmacokinetics.
Thus the bioavailability time profile is again critical in the comparison of
drugs or drug analogs. A pharmacological study is greatly enhanced by a
knowledge of the amount of the drug that has reached the receptor as a
function of time.
The concept of bioavailability in biomedical drug research, pharmaceut-
ical product development, and the rational clinical use of formulations is the
subject of this book.

REFERENCES

I. G. Carson, ON .for a Ma, TwojM a Horse, Bramhall House, New York, 1961.
2. Natitmlzl Fomudluy XVIII, American Pharmaceutical Association, Washington, D.C.,
1970.
References 5

3. Food and Drug Administration, Fed. Regisl. 38:885-a81 (1973).

4-. Guidelitwfor BiDplw.rmt~CtUlical. Studies in Mtlll, A.Ph.A. Academy of Pharmaceutical
Sciences, Washington, D.C., February 1972.
5. Pharmacokinetics and biopharmaceutics: A definition of terms, J. Plw.muu:olci~ttl.
BiDpluum. /:3 (1973).
Reference

Manual o f Symbols, Equations and Definitions in Pharmacokinetics,

Committee for Pharmacokinetic Nomenclature, American
College of Clinical Pharmacology, Philadelphia, Pennsylvania,
1982.
G. Carson, One fo r a Man, Two fo r a Horse, Bramhall House, New
York, 1961.
National Formulary XVIII, American Pharmaceutical Association,
Washington, D.C., 1970.
Food and Drug Administration, Fed. Regist. 35.885-887 (1973).
Guidelines fo r Biopharmaceutical Studies in Man, A.Ph.A.
Academy of Pharmaceutical Sciences, Washington, D.C.,
February 1972.
Pharmacokinetics and biopharmaceutics: A definition of terms, J.
Pharmacokinet. Biopharm. 1:3 (1973).
P. R. Byron, R. E. Notari, and E Tomlinson, Calculation of partition
coefficient of an unstable compound using kinetic methods. J .
Pharm. Sci., 69: 527-531 (1980).
E. Tomlinson, R. E. Notari, and P. R. Byron, Simultaneous
partitioning and hydrolysis kinetics of amoxicillin and
ampicillin. J. Pharm. Sci., 69: 655-658 (1980).
J. G. Wagner, History of pharmacokinetics. Pharm. Ther., 12: 537
(1981).
P. M. Loughnan, D. S. Sitar, R. I. Ogilvie, A. Eisen, Z. Fox, and A.
H. Neims, Pharmacokinetic analysis of the disposition of
intravenous theophylline in young children. J. Pediatr, 88: 874
(1976).
R. Nagashima, G. Levy, and R. A. O ’Reilly, Comparative
pharmacokinetics of coumarin anticoagulants. IV. Application of
a three-compartmental model to the analysis of the dose -
dependent kinetics of bishydroxycoumarin elimination. J.
Pharm. Sci., 57:1888 (1968).
L. A. Pagliaro and L. Z. Benet, Criticial compilation of terminal
half-lives, percent excreted unchanged, and changes of half-life
in renal and hepatic dysfunction for studies in humans with
references. J . Pharmacokinet. Biopharm. 3: 333 (1975).
T. R. Simpson and J. P. Juergens, Biological half-life and rational
drug therapy. Hosp. Pharm., 8:68 (1973).
W. A. Ritschel, Biological half-lives of drugs. Drug Intell. Clin.
Pharm., 4:322 (1970).
R. S. Lott and W. L. Hayton, Estimation of creatinine clearance
from serum creatinine concentration. Drug Intell. Clin. Pharm.,
12: 140 (1978).
H. Homeida, C. Roberts, and R. A. Branch, Influence of probenecid
and spironolactone on furosemide kinet cs and dynamics in
man. Clin. Pharmacol. Ther., 22:402 (1977).
J. G. Wagner, Do you need a pharmacokinetic model, and if so,
which one? J. Pharmacokinet. Biopharm., 5:457 (1975).
L. Z. Benet, General treatment of linear mammillary models with
elimination from any compartment as used in
pharmaeokinetcs. J. Pharm. Sci., 61: 536 (1972).
M. Mayersohn and M. Gibaldi, Mathematical methods in
pharmacokinetics. II. Solution of the two-compartment open
model. Am. J. Pharm. Educ., 35: 19 (1971).
A. Rescigno and G. Segre, Drug and Tracer Kinetics, Blaisdell,
Waltham, Mass, 1966, pp. 93 and 94.
R. Nagashima, G. Levy, and R. A. O ’Reilly, Comparative
pharmacokinetics of coumarin anticoagulants, IV. Application of
a three-compartmental model to the analysis of the dose-
dependent kinetics of bishydroxycoumarin elimination. J.
Pharm. Sci, 57: 1888 (1968).
P. R. Byron and R. E. Notari, Critical analysis of “flip-flop”
phenomenon in two-compartment pharmacokinetic model. J.
Pharm. Sci., 65: 1140 (1976).
R. A. Ronfield and L. Z. Benet, Interpretation of plasma
concentration-time curves after oral dosing. J .Pharm. Sci., 66:
178 (1977).
J. G. Wagner, Linear pharmacokinetic models and vanishing
exponential terms: Implications in pharmacokinetics. J.
Pharmacokinet. Biopharm., 4: 395 (1976).
D. P. Vaughan and M.J. Dennis, Number of exponential terms
describing the solution of an N -compartmental mammillary
model: Vanishing exponentials. J. Pharmacokinel. Biopharm., 7:
511 (1979).
K. K. H. Chan and M. Gibaldi, Assessment of drug absorption after
oral administration. J. Pharm. Sci., 74: 388 (1985).
R. E. Notari, J. L. DeYong, and R. H. Reuning, Effect of parallel
first-order drug loss from site of administration on calculated
values for absorption rate constants. J .Pharm. Sci., 61:135
(1972).
D. P. Vaughan and M. J. Dennis, Mathematical basis and
generalization of the Loo-Riegelman method for the
determination of in vivo drug absorption. J. Pharmacokinet.
Biopharm., 8: 83 (1980).
J. G. Wagner, Fundamentals o f Clinical Pharmacokinetics, 2nd ed.,
Drug Intelligence, Hamilton, III., 1979, p. 196.
J. G. Wagner, Pharmacokinetic absorption plots from oral data alone
or oral / intravenous data and an exact Loo-Riegelman
equation. J. Pharm. Sci., 72: 838 (1983).
K. C. Yeh and K. C. Kwan, A comparison of numerical integrating
algorithms by trapezoidal, Lagrange and spline approximation. J
. Pharmacokinet. Biopharm., 6: 79 (1978).
W. L. Chiou, Critical evaluation of the potential error in
pharmacokinetic studies of using the linear trapezoidal rule
method for the calculation of the area under the plasma level­
time curve. J .Pharmacokinet. Biopharm., 6: 539 (1978).
J. Wagner and E. Nelson, Per cent absorbed time plots derived from
blood level and/or urinary excretion data. J. Pharm. Sci., 52:610
(1963).
J. Travell, Influence of hydrogen ion concentration on absorption of
alkaloids from stomach. J. Pharmacol. Exp. Ther. 69: 21 (1940).
C. A. M. Hogben, L. S. Schanker, D. J. Tocco, and B. B. Brodie,
Absorption of drugs from the stomach. II. The human. J.
Pharmacol. Exp. Ther., 120: 540 (1957).
E. Overton. Arch. Ges. Physiol., 92:115 (1902).
Examples of sodium or potassium salts of weak acid drugs showing
increased absorption rates may be found in H. Juncher and F.
Raaschou, Antibiotic Med. Clin. Ther., 4: 497 (1957); C. C. Lee,
R. C. Anderson, F. G. Henderson, H. M. Worth, and P. N.
Harris, Antibiot. Chemother., 8: 354 (1958); and E. Nelson, J.
Pharm. Sci., 47:297 (1958).
Examples of salts of weakly basic drugs showing increased
absorption rates may be found in B. B. Brodie and C. A. M.
Hogben, J. Pharm. Pharmacol., 9 : 345 (1957); E. Nelson, J.
Pharm. Sci., 48: 96 (1959); and W. Morozowich, T. Chulski, W.
E. Hamlin, P.M. Jones, J. I. Northram, A. Purmalis, and J. G.
Wagner, J . Pharm. Sci., 51: 993 (1962).
E. Nelson, E. L. Knoechel, W. E. Hamlin, and J. G. Wagner,
Influence of the absorption rate of tolbutamide on the rate of
decline of blood sugar levels in normal humans. J. Pharm. Sci.,
51: 509 (1961).
J. R. Leonards, The influence of solubility on the rate of
gastrointestinal absorption of aspirin. Clin. Pharmacol. Ther., 4:
476 (1963), and references therein.
L. E. Hollister, Measuring Measurin: Problems of oral prolonged-
action medications. Clin. Pharmacol. Ther., 31: 1 (1972).
E. B. Truitt and A. M. Morgan, Gastrointestinal factors in aspirin
absorption. J . Pharm. Sci., 53: 129 (1964); Evaluation of
acetylsalicylic acid esterase in aspirin metabolism, J. Pharm.
Sci., 54: 1640 (1965).
J. Haleblian and W. McCrone, Pharmaceutical applications of
polymorphism. J. Pharm. Sci., 58 : 911 (1969).
J. W. Poole, G. Owen, J. Silverio, J.N. Freyhof, and S. B.
Rosenman, Trihydrate forms of ampicillin. Curr. Ther. Res., 10:
292 (1968).
J. R. Marvel, D. A. Schichting, and C. Denten, The effect of a
surfactant and particle size on griseofulvin plasma levels. J .
Invest. Dermatol., 42: 197 (1964).
M. Kraml, J. Dubuc, R. Gaudrey, and D. Beall, Gastrointestinal
absorption of griseofulvin. II. Antibiot. Chemother., 12:239
(1962); Gastrointestinal absorption of griseofulvin. I. Arch.
Dermatol., 87: 179 (1963).
R. G. Crounse, Effect of use of griseofulvin. Arch. Dermatol.,
57:176 (1963).
H. E. Paul, K.J. Hayes, M. F. Paul, and A. R. Borgmann, Laboratory
studies with nitrofurantoin. J. Pharm. Sci., 56:882 (1967).
J. D. Conklin and F.J. Hailey, Urinary drug excretion in man during
oral dosage of different nitrofurantoin formulations. Clin.
Pharmacol. Ther., 10: 534 (1969).
F. J. Hailey and H. W. Glascock, Gastrointestinal tolerance to a new
macrocrystalline form of nitrofurantoin: A collaborative
study. Curr. Ther. Res., 9:600 (1967).
J. Lindenbaum, D. G. Rund, V. P., Butler, Jr., D. Tse-Eng, and J. R.
Saha, Inactivation of digoxin by the gut flora. N.Engl. J. Med.,
305:789 (1981).
J. F. Dobkin, J. R. Saha, V. P. Butler, Jr., H. C. Neu, and J.
Lindenbaum, Digoxin-inactivating bacteria—Identification in
human gut flora. Science, 22:325 (1983).
J. G. Wagner, W. Veldkamp, and S. Long, Enteric coatings. IV. J.
Pharm. Sci., 49: 128 (1960).
J. G. Wagner, Biopharmaceutics: Absorption aspects. J. Pharm. Sci.,
50:359 (1961).
V. C. Stephens, J. W. Conine, and H. W. Murphy, Esters of
erythromycin. IV. J. Pharm. Sci., 48:620 (1959).
R. S. Griffith and H. R. Black, A comparison of blood levels after
oral administrations of erythromycin and erythromycin
estolate. Antibiot. Chemother., 12- 398 (1962).
P. H. Tardrew, J. C. H. Mao, and D. Kenny, Antibacterial activity of
2 ’-esters of erythromycin. Appl. Microbiol., 18: 159 (1969).
V. C. Stephens, C. T. Pugh, and N. E. Davis, A study of the
behavior of propionyl erythromycin in blood by a new
chromatographic method. J. Antibiot. Tokyo, 22:551 (1969).
W. E. Wick and G. E. Malitt, New analysis for the therapeutic
efficacy of propionyl erythromycin and erythromycin
base. Antimicrob. Agents Chemother., 410 (1968).
J. A. Gronroos, H. A. Saarimaa, and J. L. Kalliomaki, A study of
liver function during erythromycin estolate treatment. Curr.
Ther. Res., 9: 589 (1967), and leading references.
L. S. Goodman and A. Gilman, The Pharmacological Basis o f
Therapeutics, 4th ed., MacMillan, New York, 1970, p. 1040.
R. G. Remmers, G. M. Sieger, N. Anagnostakos, J. C. Corbett, and
A. P. Doerschuk, Metal-acid complexes with members of the
tetracycline family. III. J. Pharm. Sci., 54:49 (1965), and
references therein.
J. Scheiner and W. A. Altemeier, Experimental study of factors
inhibiting absorption and effective therapeutic levels of
declomycin. Surgery, 114:9 (1962).
The following reviews have summarized observed differences in
product bioavailability: J. G. Wagner, Generic equivalence and
inequivalence of oral products. Drug Intell. Clin. Pharmacol., 5
:115 (1971); Symposium on formulation factors affecting
therapeutic performance of drug products. Drug Inform. Bull., 3
(1969); Bioavailability o f Drugs ( B. B. Brodie and W. M.
Heller, eds.), S. Karger, New York, 1972; and Anonymous,
Biological availability, a statement by the Pharmaceutical
Society of Great Britain. Drug Intell. Clin. Pharm., 7:117
(1973).
(a) A. J. Aguiar, L. M. Wheeler, S. Fusari, and J. E. Zelmer,
Evaluation of physical and pharmaceutical factors involved in
drug release and availability from chloramphenicol
capsules. J.Pharm. Sci., 57:1844 (1968); (b) A.J. Glazko, A. W.
Kinkel, W. C. Alegnani, and E. L. Holmes, An evaluation of the
absorption characteristics of different chloramphenicol
preparations in normal human subjects. Clin. Pharmacol. Ther.,
9:472 (1968).
P. R. Byron and R. E. Notari, Critical analysis of “flip-flop”
phenomenon in two-compartment pharmacokinetic model. J.
Pharm. Sci., 65: 1140 (1976).
L. Hendeles, K. Thakker, and M. Weinberger, Food-induced dose
dumping of Theo-24. Am. Pharm., NS25 : 10 (1985).
E. Cuenca, E. Costa, R. Kuntzman, and B. B. Brodie, The methyl
ether of methyl reserpate; a prototype of reversible short-acting
tranquilizing agents. Med. Exp., 5:20 (1961).
L. E. Hollister, Studies of delayed-action medications. N. Engl. J.
Med., 266:281 (1962); Curr. Ther. Res., 4: 471 (1962); Clin.
Pharmacol. Ther., 4: 612 (1963).
L. Hollister and G. Levy, Some aspects of salicylate distribution and
metabolism in man. J. Pharm. Sci., 54:1126 (1965).
J. C. King, Clinical experience with a new long-acting antacid-
anticholinergic preparation. Am. J. Gastroenterol., 32:509
(1959).
J. R. Robinson (ed.), Sustained and Controlled Release Drug
Delivery Systems, Marcel Dekker, New York, 1978.
E. Kruger-Thiemer, Formal theory of drug dosage regimens. I. J.
Theor. Biol., 13: 212 (1966).
E. Kruger-Thiemer, Formal theory of drug dosage regimens. II. The
exact plateau effect. J. Theor. Biol., 23 : 169 (1969).
E. Kruger-Thiemer, P. Bunger, L. Dettli, P. Spring, and E. Wempe,
Dosage regimen calculation of chemotherapeutic agents. Part III.
Sulfasymazine. Chemotherapia, 10: 325 (1965/66); see
also Chemotherapia, 10: 61, 129 (1965) for Parts 1 and 2.
M. Gibaldi and D. Perrier, Pharmacokinetics, Marcel Dekker, New
York, 1975, p. 101.
P. R. Byron and R. E. Notari, Critical analysis of “flip-flop”
phenomenon in two-compartment pharmacokinetic model. J .
Pharm. Sci., 65 : 1140 (1976).
R. E. Notari, M.-Y. Huang, and P. R. Byron, Calculations of
Optimum Pharmacokinetic Drug Supply Rates for Maximum
Duration During Multiple Dose Therapy by Prodrug
Administration, Int. J. Pharm. 1, 233 (1978).
J. G. Wagner, J. I. Northram, C. D. Alway, and O.S. Carpenter,
Blood levels of drug at the equilibrium state after multiple
dosing. Nature, 207: 1301 (1965).
M. Gibaldi and H. Weintraub, Some considerations as to the
determination and significance of biological half-life. J. Pharm.
Sci., 60: 624 (1971).
D. Perrier and M. Gibaldi, Relationship between plasma or serum
drug concentration and amount of drug in the body at steady
 state upon multiple dosing. J. Pharmacokinet. Biopharm., 1 : 17
(1973).
G. E. Schumacher, Practical pharmacokinetic techniques for drug
consultation and evaluation. I. Use of dosage regimen
calculations. Am. J. Hosp. Pharm., 29: 474 (1972).
E. Kruger-Thiemer, Dosage schedule and pharmacokinetics in
chemotherapy. J. Pharm. Sci., 49: 311 (1960).
J. M. Van Rossum, Pharmacokinetics of accumulation. J. Pharm.
Sci., 57: 2162 (1968).
J. G. Wagner, Pharmacokinetics, J. M. Richard Laboratory, Grosse
Pointe Park, Mich., 1969, p. 139.
P. J. Niebergall, E. T. Sugita, and R. L. Schnaare, Calculation of
plasma versus time profiles for variable dosing regimens. J.
Pharm. Sci., 63 : 100 (1974).
C. L. Winek, A role for the hospital pharmacist in toxicology and
drug blood level information. Am. J. Hosp. Pharm., 28 : 351
(1971).
J. Fabre and L. Balant, Renal failure, drug pharmacokinetics and
drug action. Clin. Pharmacokinet., 1 : 99 (1976).
W. M. Bennett, I. Singer, and C. H. Coggins, A practical guide to
drug usage in adult patients with imparied renal function. J. Am.
Med. Assoc., 214: 1468 (1970); see also Guide to drug usage in
adult patients with impaired renal function. A Supplement. J.
Am. Med. Assoc., 223: 991 (1973).
L. Dettli, Elimination kinetics and dosage adjustment of drugs in
patients with kidney disease. Prog. Pharmacol., 1, No. 4 (1977).
L. Dettli, Drug dosage in renal disease. Clin. Pharmacokinet., 1 :
126 (1976).
Litton Industries, Physician ’s Desk Reference, 39th ed., Oradell,
N.J., 1985, p. 1854.
Dias Rounds, Request Number 4, Drug Intell. Clin. Pharm., 5: 251
(1971).
C. S. Lee, J. G. Gambertoglio, D. C. Brater, and L. Z. Benet,
Kinetics of oral ethambutol in the normal patient. Clin.
Pharmacol. Ther., 22: 615 (1977).
A. M. Burkman, R. E. Notari, and W. K. VanTyle, Structural effects
in drug distribution: Comparative pharmacokinetics of
apomorphine analogs. J. Pharm. Pharmacol., 26: 493-507
(1974).
K. H. Spitzy and G. Hitzenberger, The distribution volume of some
antibiotics. Antibiot. Annu. 996 (1957-1957).
R. Pratt, Antibiotics 1956-1961. J. Pharm. Sci., 51: 1 (1964).
C. M. Kunin, Pharmacology of the antimicrobials. Mod. Treat., 7:
829 (1964).
G. H. Warren, The prognostic significance of penicillin serum levels
and protein binding in clinical medicine. Chemotherapia, 10 :
339 (1966).
J. P. Hou and J. W. Poole, ß -Lactam antibiotics: Their
physicochemical properties and biological activities in relation
to structure. J. Pharm. Sci., 60: 503 (1971).
J. Fabre, E. Milek, P. Kalfopoulos, and G. Merier, Schweitz. Med.
Wochenschr. 707: 625 (1971).
E. P. Abraham, Advances in Pharmaceutical Sciences, Vol. 1 ( D.
Perlman, ed.), Wiley, New York, 1967, pp. 1-31.
K. E. Price, A. Gourevitch, and L. C. Cheney, Biological properties
of semisynthetic penicillins: Structure-activity
relationships. Antimicrob. Agents Chemother., 670 (1966).
E. Kaczka and K. Folkers, in The Chemistry o f Penicillin ( H. T.
Clarke, J. R. Johnson, and B. Robinson, eds.), Princeton
University Press, Princeton, N.J., 1949, pp. 243-268.
M. A. Schwartz and F. H. Buckwalter, Pharmaceutics of
penicillin. J. Pharm. Sci., 51 : 1119 (1962).
Z. Modr and K. Dvoracek, in Advances in Biosciences ( G. Raspe,
ed.), Pergamon, Elmsford, N.Y., 1970, p. 219.
J. E. Rosenblatt, A. C. Kind, J. L. Brodie, and W. M. M. Kirby,
Mechanisms responsible for the blood level differences of
isoxazolyl penicillins. Arch. Intern. Med., 121: 345 (1968).
C. F. Gravenkemper, J. V. Bennett, J. L. Brodie, and W. M. M.
Kirby, Dicloxacillin. In vitro and pharmacologic comparisons
with oxacillin and cloxacillin. Arch. Intern. Med., 116: 340
(1965).
L. W. Dittert, W. O. Griffin, J. C. LaPiana, F.J. Shainfeld, and J. T.
Doluisio, Pharmacokinetic interpretation of penicillin levels in
serum and urine after intravenous administration. Antimicrob.
Agents Chemother., 42 (1969).
H. C. Standiford, M. C. Jordan, and W. M. M. Kirby, Clinical
pharmacology of carbenicillin compared with other
penicillins. J. Infect. Dis. Suppl., 122: 9 (1970).
J. H. C. Nayler, Structure-activity relationships in semi-synthetic
penicillins. Proc. R. Soc. London, 179: 357 (1971).
E. H. Nauta and H. Mattie, Dicloxacillin and cloxacillin:
Pharmacokinetics in healthy and hemodialysis subjects. Clin.
Pharmacol. Ther., 20, 98-108 (1976).
W. J. Jusko and G. P. Lewis, Comparison of ampicillin and
hctacillin pharmacokinetics in man. J. Pharm. Sci., 62: 69
(1973).
D. Zarowny, R. Ogilvie, D. Tamblyn, C. MacLeod, and J. Reudy,
Pharmacokinetics of amoxicillin. Clin. Pharmacol. Ther., 16:
1045 (1974).
A. Philipson, L.D. Sabath, and B. Rosner, Sequence effect on
ampicillin blood levels noted in an amoxicillin, ampicillin and
epicillin triple crossover study. Anlimicrob. Agents
Chemother., 8: 311 (1975).
R. D. Libke, J. T. Clarke, E. D. Ralph, R. P. Luthy, and W. M. M.
Kirby, Ticarcillin vs. carbenicillin: Clinical
pharmacokinetics. Clin. Pharmacol. Ther., 17: 441 (1975).
K. Roholt, Pharmacokinetic studies with mecillinam and
pivmecillinam. J. Anlimicrob. Chemother. Suppl. B, 3: 71
(1977).
L. J. Leeson, J. E. Krueger, and R. A. Nash, Concerning the
structural assignments of the second and third acidity constants
of the tetracycline antibiotics. Tetrahedron Lett., 18: 1155
(1963).
W. H. Barr, J. Adir, and L. Garrettson, Decrease in tetracycline
absorption in man by sodium bicarbonate. Clin. Pharmacol.
Ther., 12: 779 (1971).
M. Barza, R. B. Brown, C. Shanks, C. Gamble and L. Weinstein,
Relation between lipophilicity and pharmacological behavior of
minocycline, doxycycline, tetracycline and oxytetracycline in
dogs. Antimicrob. Agents Chemother., 8: 713 (1975).
J. Scheiner and W. A. Altemeir, Experimental study of factors
inhibiting absorption and effective therapeutic levels of
declomycin. Surgery, 114: 9 (1962).
L. A. Mitscher, A. C. Bonacci, and T. D. Sokoloski, Circular
dichroism and solution conformation of the tetracycline
antibiotics. Tetrahedron Lett., 51: 5361 (1968).
N. A. Baker and P. M. Brown, Metal binding in tetracyclines—
Cobalt (II) and nickel (II) complexes.J. Am. Chem. Soc., 88:
1314 (1966).
L. Z. Benet and J. E. Goyan, Thermodynamics of chelation by
tetracyclines. J. Pharm. Sci., 55: 1184 (1966).
J. E. Rosenblatt, J. E. Barrett, J. L. Brodie, and W. M. M. Kirby,
Comparison of in vitro activity and clinical pharmacology of
doxycycline with other tetracyclines. Anlimicrob. Agents
Chemother., 134 (1966).
P. G. Welling, P. A. Koch, C. C. Law, and W. A. Craig,
Bioavailability of tetracycline and doxycycline in fasted and
nonfasted subjects. Antimicrob. Agents Chemother., 11: 462
(1977).
C. M. Kunin, Blood level measurements and antimicrobial
agents. Clin. Pharmacol. Ther., 16: 251 (1974).
W. J. Jusko and M. Gretch, Plasma and tissue protein binding of
drugs in pharmacokinetics. DrugMetab. Rev., 5: 43 (1976).
J. Koch-Weser and E. M. Sellers, Binding of drugs to serum
albumin. Med. Intell., 294:311, 526 (1976).
R. C. Batterman, L. F. Tauber, and M. E. Bell, Long-acting
sulfonamides: In vivo correlation in man of protein binding,
serum concentration and antimicrobial activity. Curr. Ther.
Res., 8: 75 (1966).
C. M. Kunin, Clinical pharmacology of the new penicillins. 1. The
importance of serum protein binding in determining
antimicrobial activity and concentration in serum. Clin.
Pharmacol. Ther., 7: 166 (1966).
M. C. Meyer and D. E. Guttman, The binding of drugs by plasma
proteins. J. Pharm. Sci., 57: 895 (1968).
M. Schach von Wittenau and T. M. Twomey, The disposition of
doxycycline by man and dog. Chemotherapy, 16: 217 (1971).
H. MacDonald, R. G. Kelly, E. S. Allen, J. F. Noble, and L. A.
Kangis, Pharmacokinetic studies on minocycline in man. Clin.
Pharmacol. Ther., 14 : 852 (1973).
P. G. Welling, W. R. Shaw, S. J. Uman, F. L. S. Tse, and W. A.
Craig, Pharmacokinetics of minocycline in renal
failure. Antimicrob, Agents Chemother., 8: 532 (1975).
J. T. Doluisio and L. W. Dittert, Influence of repetitive dosing of
tetracyclines on biologic half-life in serum. Clin. Pharmacol.
Ther, 10: 690 (1969).
M. Gibaldi and H. Weintraub, Some considerations as to the
determination and significance of biological half-life. J. Pharm.
Sci., 60: 624 (1971).
M. Barza and R. T. Scheife, Drug therapy reviews: Antimicrobial
spectrum, pharmacology and therapeutic use of antibiotics. Part
4. Aminoglycosides. Am. J. Hosp. Pharm., 34: 723 (1977).
F. C. Luft, Netilmicin: A review of toxicity in laboratory animals. J.
Intern. Med. Res., 6: 286 (1978).
P. J. S. Chiu, A. Brown, G. Miller, and J. F. Long, Renal extraction
of gentamicin in anesthetized dogs. Antimicrob. Agents
Chemother., 10 : 277 (1976).
R. Nedden, T. Fuchs, K. Schroder, and W. Wundt, Die renale
Ausscheidung von Gentamicin beim Menschen, Dtsch. Med.
Wochenschr., 97: 1496 (1972).
P. J. S. Chiu, G. H. Miller, A. D. Brown, J. F. Long, and J. A.
Wartz, Renal pharmacology of netilmicin. Antimicrob. Agents
Chemother., 11: 821 (1977).
J. J. Schentag and W. J. Jusko, Renal clearance and tissue
accumulation of gentamicin. Clin. Pharmacol. Ther., 22: 364
(1977).
J. J. Schentag, G. Lasezkay, T. J. Cumbo, M. E. Plaut, and W. J.
Jusko, Accumulation pharmacokinetics of
tobramycin. Antimicrob. Agents Chemother., 13 : 649 (1978).
J.-C. Pechere, R. Dugal, and M.-M. Pechere, Kinetics of netilmicin
in man. Clin. Pharmacol. Ther., 23: 677 (1978).
J. A. Jahre, K. P. Fu, and H. C. Neu, Kinetics of netilmicin and
gentamicin. Clin. Pharmacol. Ther., 23: 591 (1978).
G. Kahlmeter and C. Kamme, Prolonged excretion of gentamicin in
a patient with unimpaired renal function. Lancet, Feb. 1, 286
(1975).
H. Wahlig, G. Langenberg, and D. von Kobyletzki, Erganzende
Untersuchun-gen zur Pharmakokinetik von
Gentamicin. Infection, 5: 217 (1975).
J. J. Schentag, W. J. Jusko, M. E. Plaut, T. J. Cumbo, J. W. Vance,
and E. Abrutyn, Tissue persistence of gentamicin in man. J. Am.
Med. Assoc., 238 : 327 (1977).
G. Kahlmeter, S. Jonsson, and C. Kamme, Longstanding post-
therapeutic gentamicin serum and urine concentrations in
patients with unimpaired renal function: A pharmacokinetic
evaluation. J. Antimicrob. Chemother., 4: 143 (1978).
F. Follath, P. Spring, M. Wenk, L. Z. Benet, and L. Dettli,
Comparative pharmacokinetics of sisomicin and netilmicin in
healthy volunteers. Proc. 10thInt. Congr. Chemother., Vol. 2,
Zurich, 1977, p. 979.
G. Kahlmeter, S. Jonsson, and C. Kamme, Multiple-compartment
pharmacokinetics of tobramycin. Proc. 10th Int. Congr.
Chemother., Vol. 2, Zurich, 1977, p. 912.
C. Q. Edwards, C. R. Smith, K. L. Baughman, J. F. Rogers, and P.
S. Lietman, Concentrations of gentamicin and amikacin in
human kidneys. Antimicrob. Agents Chemother., 9: 925 (1976).
B. R. Meyers and S. Z. Hirschman, Pharmacologic studies on
tobramycin and comparison with gentamicin. J. Clin.
Pharmacol., 12 : 321 (1972).
H. Lode, B. Kemmerich, and P. Koeppe, Comparative clinical
pharmacology of gentamicin, sisomicin and
tobramycin. Antimicrob. Agents Chemother., 8: 396 (1975).
J. Levy and J. Klastersky, Correlation of serum creatinine
concentration and amikacin half-life. J. Clin. Pharmacol., 75:
705 (1975).
J. T. Clarke, R. D. Libke, C. Regamey, and W. W. Kirby,
Comparative pharmacokinetics of amikacin and
kanamycin. Clin. Pharmacol. Ther., 75: 610 (1974).
M. Barza, R. B. Brown, D. Shen, M. Gibaldi, and L. Weinstein,
Predictability of blood levels of gentamicin in man. J. Infect.
Dis., 132 : 165 (1975).
B. M. Orme and R. E. Cutler, The relationship between kanamycin
pharmacokinetics: Distribution and renal function. Clin.
Pharmacol. Ther., 70: 543 (1969).
J. T.Doluisio, L. W. Dittert, and J. C. LaPiana, Pharmacokinetics of
kanamycin following intramuscular
administration. J.Pharmacokinet. Biopharm., 7: 253 (1973).
B.-S. Yap, D. Stewart, and G. P. Bodey, Clinical pharmacology of
netilmicin. Antimicrob. Agents Chemother., 12 : 717 (1977).
G. Humbert, A. Leroy, J. P. Fillastre, and G. Oksenhendler,
Pharmacokinetics of netilmicin in the presence of normal or
impaired renal function. Antimicrob. Agents Chemother., 14: 40
(1978).
I. Trestman, J. Parsons, J. Santoro, G. Goodhart, and D. Kaye,
Pharmacology and efficacy of netilmicin. Antimicrob. Agents
Chemother., 73 : 832 (1978).
B. R. Meyers, S. Z. Hirschman, G. Wormser, and D. Siegel,
Pharmacokinetic study of netilmicin. Antimicrob. Agents
Chemother., 72: 122 (1977).
F. Meunier-Carpentier, M. Staquet, and J. Klastersky, Comparative
study of three routes of administration of sisomicin. J. Clin.
Pharmacol., 16 : 625 (1976).
B. R. Meyers, S. Z. Hirschman, S. Yancovitz, and B. Ribner,
Pharmacokinetic parameters of sisomicin. Antimicrob. Agents
Chemother., 10: 25 (1976).
E. H. Flynn, ed., Cephalosporins and Penicillins, Chemistry and
Biology, Academic, New York, 1972.
G. H. Constantine, Antibiotic chemotherapy. Pharm. Index, 18 : 13
(1976).
C. H. Nightingale, D. S. Greene, and R. Quintiliani,
Pharmacokinetics and clinical use of cephalosporin antibiotics. J
. Pharm. Sci., 64: 1899 (1975).
B. E. Cabana, D. R. Van Harken, G. H. Hottendorf, J. T. Doluisio,
W. O. Griffin, D. W. A. Dourne, and L. W. Dittert, The role of
the kidney in the elimination of cephapirin in man. J.
Pharmacokinet. Biopharm., 3 : 419 (1975).
D. A. Spyker, B. L. Thomas, M. A. Sande, and W. Kline Bolton,
Pharmacokinetics of cefaclor and cephalexin: Dosage
nomograms for impaired renal function. Antimicrob. Agents
Chemother., 14 : 172 (1978).
O. M. Korzeniowski, W. M. Scheld, and M. A. Sande, Comparative
pharmacology of cefaclor and cephalexin. Antimicrob. Agents
Chemother., 12 : 157 (1977).
P. Actor, D. H. Pitkin, G. Lucyszyn, J. A. Weisbach, and J. L. Bran,
Cefatrizine (SKF 60771), a new oral cephalosporin: Serum
levels and urinary recovery in humans after oral or intramuscular
administration: Comparative study with cephalexin and
cefazolin. Antimicrob Agents Chemother., 9: 800 (1976).
M. Pfeffer, A. Jackson, J. Zimenes, and J. P. DeMenezes,
Comparative human oral clinical pharmacology of cefadroxil,
cephalexin and cephradine. Antimicrob. Agents
Chemother., 11:331 (1977).
R.J. Fuss and R. B. Prior, Comparative in vitro activities of oral
cephalosporins and competitive antibiotics against recent clinical
isolates. Curr. Ther. Res., 24: 352 (1978).
R. Bloch, J. J. Szwed, R. S. Sloan, and F. C. Luft, Pharmacokinetics
of cefaclor in normal subjects and patients with chronic renal
failure. Antimicrob. Agents Chemother., 12 : 730 (1977).
M. Barza, S. Melethil, S. Berger, and E. C. Ernst, Comparative
pharmacokinetics of cefamandole, cephapirin, and cephalothin
in healthy subjects and effect of repeated dosing. Antimicrob.
Agents Chemother., 10 : 421 (1976).
Physician ’s Desk Reference, 39th ed., Medical Economics, Oradell,
N.J., 1985.
H.-E. Mellin, P. G. Welling, and P.O. Madsen, Pharmacokinetics of
cefamandole in patients with normal and impaired renal
function. Antimicrob. Agents Chemother., 11 : 262 (1977).
E. S. Rattie and L. J. Ravin, Pharmacokinetic interpretation of blood
levels and urinary excretion data for cefazolin and cephalothin
after intravenous and intramuscular administration in
humans. Antimicrob. Agents Chemother., 7: 606 (1975).
J. B. deMaine and W. M. M. Kirby, Clinical pharmacology of
cephalexin administered intravenously. Antimicrob. Agents
Chemother., 190 (1970).
L. A. Pagliaro and L. Z. Benet, Critical compilation of terminal half­
lives, percent excreted unchanged and changes in half-life in
renal and hepatic dysfunction for studies in humans with
references. J . Pharmacokinet. Biopharm., 5: 333 (1975).
A. I. Hartstein, K. E. Patrick, S. R. Jones, M. J. Miller, and R. E.
Bryant, Comparison of pharmacological and antimicrobial
properties of cefadroxil and cephalexin. Antimicrob. Agents
Chemother., 12: 93 (1977).
I. W. Fong, E. D. Ralph, E. R. Engelking, and W. M. M. Kirby,
Clinical pharmacology of cefamandole as compared with
cephalothin. Antimicrob. Agents Chemother., 9: 65 (1976).
B. R. Meyers, B. Ribner, S. Yancovitz, and S. Z. Hirschman,
Pharmacological studies with cefamandole in human
volunteers. Antimicrob. Agents Chemother., 9: 140 (1976).
M. C. Nahata and D. A. Powell, Bioavailability and clearance of
chloramphenicol after intravenous chloramphenicol
succinate. Clin. Pharmacol. Ther., 30: 368-372 (1981).
J. T. Burke, W. A. Wargin, R. J. Sheretz, K. L. Sanders, M. R.
Blum, and F. A. Sarubbi, Pharmacokinetics of intravenous
chloramphenicol sodium succinate in adult patients with normal
renal and hepatic function. J. Pharmacokinet. Biopharm., 10:
601-614 (1982).
R. E. Kauffman, M. C. Thirumoorthi, J. A. Buckley, M. K. Aravind,
and A. S. Dajani, Relative bioavailability of intravenous
chloramphenicol succinate and oral chloramphenicol palmitate
in infants and children. J. Pediatr., 99: 963-967 (1981).
W. J. Jusko, G. P. Lewis, and G. W. Schmitt, Ampicillin and
hetacillin pharmacokinetics in normal and anephric
subjects. Clin. Pharmacol. Ther., 14: 90 (1973).
W. J. Jusko and G. P. Lewis, Precaution in pharmacokinetic
evaluation of ampicillin precursors. Lancet, 1: 690 (1972).
J. C. K. Loo, E. L. Foltz, H. Wallick, and K. C. Kwan,
Pharmacokinetics of pivampicillin and ampicillin in man. Clin.
Pharmacol. Ther., 16: 35 (1974).
B. Lund, J. P. Kampmann, F. Lindahl, and J. M. Hansen,
Pivampicillin and ampicillin in bile, portal and peripheral
blood. Clin. Pharmacol. Ther., 79: 587 (1976).
A. Swahn, Ph.D. thesis, Department of Medicine and Clinical
Pharmacology, Karolinska Institutet, Stockholm, 1974, p. 13.
M. Rozencweig, M. Staquet, and J. Klastersky, Antibacterial activity
and pharmacokinetics of bacampicillin and ampicillin. Clin.
Pharmacol. Ther., 79: 592 (1976).
N.-O. Bodin, B. Ekstrom, U. Forsgren, L.-P. Jalar, L. Magni, C.-H.
Ramsay, and B. Sjoberg, Bacampicillin: A new orally well-
absorbed derivative of ampicillin. Antimicrob. Agents
Chemother., 8 : 518 (1975).
J. P. Clayton, M. Cole, S. W. Elson, and H. Ferres, BRL. 8988
(talampicillin): A well absorbed oral form of
ampicillin. Antimicrob. Agents Chemother., 5: 670-671 (1974).
J. P. Clayton, M. Cole, S. W. Elson, H. Ferres, J. C. Hanson, L. W.
Mizen, and R. Sutherland, Preparation hydrolysis and oral
absorption of lactonyl esters of penicillins. J. Med. Chem., 19:
1385 (1976).
Y. Shiobara, A. Tachibana, H. Sasaki, T. Watanabe, and T. Sado,
Phthalidyl D-a-aminobenzylpenicillinate hydrochloride (PC-
183): A new orally active ampicillin ester. J. Antibiot., 27: 665
(1974).
M. Ehrnebo, S. Nilsson, and L. O. Boreus, Pharmacokinetics of
ampicillin and its prodrugs bacampicillin and pivampicillin in
man. J. Pharmacokinet. Biopharm., 7: 429-451 (1979).
W. von Daehne, W. O. Godtfredsen, K. Roholt, and L. Tybring,
Pivampicillin, a new orally active ampicillin ester. Antimicrob.
Agents Chemother., 431 (1970).
I. Isaka, K. Nakano, T. Kashiwagi, A. Koda, H. Horiguchi, H.
Matsui, K. Takahashi, and M. Murakami, Lactol esters of
ampicillin. Chem. Pharm. Bull., 24: 102 (1976).
J. Sjovall, L. Magni and T. Bergan, Pharmacokinetics of
bacampicillin compared with those of ampicillin, pivampicillin
and amoxycillin. Antimicrob. Agents Chemother., 13 : 90 (1978).
T. Bergan, Pharmacokinetic comparison of oral bacampicillin and
parenteral ampicillin. Antimicrob. Agents Chemother., 13 : 971
(1978).
J. S. Tan and S.J. Salstrom, Bacampicillin, ampicillin, cephalothin,
and cephapirin levels in human blood and interstitial
fluid. Antimicrob. Agents Chemother., 75: 510-512 (1979).
A. P. Ball, A. K. Viswan, M. Mitchard, and R. Wise, Plasma
Concentrations and Excretion of Mecillinam After Oral
Administration of Pivmecillinam in Elderly Patients, J.
Antimicrob. Chemother. 4, 241 (1978).
D. Westerlund, B. Pettersson, and J. Carlqvist, Determination of
bacmecillinam, an amdinocillin prodrug in human and canine
whole blood by reversed-phase liquid chromatography. J Pharm.
Sci., 71: 1148-1151 (1982).
V. C. Stephens, C. T. Pugh, N. E. Davis, M. M. Hoehn, S. Ralston,
M. C. Sparks, and L. Thompkins, A study o f the behavior o f
 propionylerythromycin in blood by a new chromatographic
method, 8th Intersci. Conf. Antimicrob. Ag. Chemother., N.Y.,
October 21-23. (1968). Data are summarized in New Studies
Reaffirm Consistent Absorption, Dependable Antibacterial
Activity o f llosone, Erythromycin Estolate, Eli Lilly and Co.,
Indianapolis, 1968.
V. C. Stephens, C. T. Pugh, N. E. Davis, M. M. Hoehn, S. Ralston,
M. C. Sparks, and L. Thompkins, A study of the behavior of
propionylerythromycin in blood by a new chromatographic
method. J. Antibiot., 22: 551 (1969).
P. G. Welling, R. L. Elliott, M. E. Pitterle, H. P. Corrick-West, and
L. L. Lyons, Plasma levels following single and repeated doses
of erythromycin estolate and erythromycin stearate. J . Pharm.
Sci., 68: 150-155 (1979).
A. R. DiSanto, K. Y. Tserng, D.J. Chodos, K. A. DeSante, K. S.
Albert, and J. G. Wagner, Comparative bioavailability
evaluation of erythromycin base and its salts and esters. I.
Erythromycin estolate capsules versus enteric-coated
erythromycin base tablets. J. Clin. Pharmacol., 20: 437-443
(1980).
G.J. Yakatan, C. E. Rasmussen, P.J. Feis, and S. Wallen,
Bioinequivalence of erythromycin ethylsuccinate and enteric-
coated erythromycin pellets following multiple oral doses. J.
Clin. Pharmacol., 25: 36-42 (1985).
S. H. Curry and R. Whelpton, Kinetics of fluphenazine after
fluphenazine dihydrochloride, enanthate and decanoate
administration to man. Br. J. Clin. Pharmacol., 7: 325-331
(1979).
P. R. Byron and R. E. Notari, Critical analysis of “flip-flop”
phenomenon in two-compartment pharmacokinetic model. J.
Pharm. Sci., 65 : 1140 (1976).
P. R. Byron, R. E. Notari, and M.-Y. Huang, Pharmacokinetic
predictions of optimum drug delivery rates from prodrugs
designed for maximum duration. Int.J.Pham., 1 : 219 (1978).
R. E. Notari, M.-Y. Huang, and P. R. Byron, Calculations of
optimum pharmacokinetic drug supply rates for maximum
duration during multiple dose therapy by prodrug
administration. Int. J. Pharm., 1 : 233 (1978).
D. H. Ho, V. Rodriguez, T. L. Loo, G. P. Bodey, and E.J. Freireich,
Clinical pharmacology of 02, 2 ’-cyclocytidine. Clin. Pharmacol.
Ther., 17 : 66 (1975).
A. Tsuji, E. Miyamoto, T. Terasaki, and T. Yamana, Carbenicillin
prodrugs: Stability kinetics of a-phenyl and a-indanyl esters in
aqueous solution. J. Pharm. Sci., 68: 1259-1263(1979).
E. Pawelczyk, M. Zajac, B. Knitter, and P. Mikolajczak, Kinetics of
drug decomposition. Part 66. Kinetics of the hydrolysis of
carphecillin in aqueous solution. Pol. J. Pharmacol. Pharm. 33:
373-386 (1981).
T. Bergan, Penicillins. Antibiot. Chemother., 25: 1-122 (1978).
J. F. Wallace, E. Atalus, D. M. Bear, N. K. Brown, H. Clark, and M.
Turck, Evaluation of an indanyl ester of
carbenicillin. Antimicrob. Agents Chemother., 223 (1970).
R. E. Notari, Theory and practice of prodrug kinetics. Methods
Enzymol, 112A: 309 (1985).
J. S. Wold, R. R. Joost, H. R. Black, and R. S. Griffith, Hydrolysis
of cefa-mandole nafate to cefamandole in vivo. J. Infect. Dis.
Suppl, V137: 517-524 (1978).
R. E. Notari, Prodrug design. Pharm. Ther., 14: 25 (1981).
E.J. Ariens, W. Soudijn, and P. B. M. W. M. Timmermans,
eds. Stereochemistry and Biological Activity o f Drugs, Black
well Scientific, London, 1983.
M. Simonyi, On chiral drug action. Med. Res. Rev., 4 : 359 (1984).
E.J. Ariëns, Stereochemistry, a basis for sophisticated nonsense in
pharmacokinetics and clinical pharmacology. Eur. J. Clin.
Pharmacol., 25: 663 (1984).
J.J. Lima, H. Boudoulas, and B.J. Shields, Stereoselective
Pharmacokinectics of disopyramide enantiomers in man. Drug
Metab. Dispos., 13: 572 (1985).
D. D. Breimer, Pharmacokinectics o f Hypnotic Drugs, Ph.D. thesis,
University of Nijmegen, The Netherlands, 1974.
A. Brekenridge, M. Orme, H. Wesseling, R.J. Lewis, and R.
Gibbons, Pharmacokinetics and pharmacodynamics of the
enantiomers of warfarin in man. Clin. Pharmacol. Ther., 15 :
424 (1974).
D. G. Shand and R. E. Rango, The disposition of propanolol, 1.
Elimination during oral absorption in man. Pharmacology, 7:
159 (1972).
P. R. Byron, R. E. Notari, and M.-Y. Huang, Pharmacokinetic
predictions of optimum drug delivery rates from prodrugs
designed for maximum duration. Int. J. Pharm., 1: 219 (1978).
C. M. Kunin, Blook level measurements and antimicrobial
agents. Clin. Pharmacol. Ther., 16. :251 (1974).
J. R. Gilette and S. Pang, Theoretical aspects of pharmacokinetic
drug interactions. Clin. Pharmacol. Ther., 22: 623 (1977).
M. B. Kristensen, Drug interactions and clinical
pharmacokinetics. Clin. Pharmacokinet., 1:351 (1976).
M. Rowland and S. B. Matin, Kinetics of drug-drug interactions. J.
Pharmacokinet. Biopharm., 1 : 553 (1973).
W. S. Nimmo, Drugs, diseases and altered gastric emptying. Clin.
Pharmacokinet., 1: 189 (1976).
R. L. Parsons, Drug absorption in gastrointestinal disease with
particular reference to malabsorption syndromes. Clin.
Pharmacokinet., 2: 45 (1977).
P. G. Welling, Influence of food and diet on gastrointestinal drug
absorption. J. Pharmacokinet. Biopharm., 5: 291 (1977).
W. H. Barr, J. Adir, and L. Garrettson, Decrease of tetracycline
absorption in man by sodium bicarbonate. Clin. Pharmacol.
Ther., 12: 779 (1971).
P. A. Kramer, D.J. Chapron, J. Benson, and S. A. Mercik,
Tetracycline absorption in elderly patients with
achlorhydria. Clin. Pharmacol. Ther., 23: 467 (1978).
E. M. Baylis, J. M. Crowley, J. M. Preece, P. E. Sylvester, and V.
Marks, Influence of folic acid on blood phenytoin
levels. Lancet, 7: 62 (1971).
J. M. Jaffe, R. I. Poust, S. L. Feld, and J. L. Colaizzi, Influence of
repetitive dosing and altered urinary pH on doxycycline
excretion in humans. J. Pharm. Sci., 63 :1256(1974).
G. D. Bellward, P. M. Warren, W. Howald, J. E. Axelson, and F. S.
Abbott, Methadone maintenance: Effect of urinary pH on renal
clearance in chronic high and low doses. Clin. Pharmacol.
Ther., 22: 92 (1977).
H. B. Kostenbauder, J. B. Portnoff, and J. V. Swintosky, Control of
urine pH and its effect on sulfaethidole excretion in humans. J .
Pharm. Sci., 51: 1084 (1962).
M. Rowland and A. H. Beckett, The amphetamines: Clinical
pharmacokinetic implications of recent studies of an assay
procedure and urinary excretion in man. Arzneim. Forsch., 1 :
1369 (1966).
M. Gibaldi, B. Grundhofer, and G. Levy, Time course and dose
dependence of antacid effect on urine pH. J. Pharm.
Sci., 64:2003 (1975).
J. B. Field, M. Ohta, C. Boyle, and A. Remers, Potentiation of
acetohexamide hypoglycemia by phenylbutzaone. N. Engl. J.
Med., 277: 889 (1967).
D. D. Breimer and E. Richter, Pharmacokinetic interactions with
rifampicin. Clin. Pharmacokinet., 2: 61 (1977).
W. J. Jusko and M. Gretch, Plasma and tissue protein binding of
drugs in pharmacokinetics. DrugMetab. Rev., 5: 43 (1976).
J. Koch-Weser and E. M. Sellers, Binding of drugs to serum
albumin. Med. Intell., 29:311,526 (1976).
L. B. Wingard, Jr., R. A. O ’Reilly, and G. Levy, Pharmacokinetics
of warfarin enantiomers: A search for intrasubject
correlations. Clin. Pharmacol. Ther., 23 : 212 (1978), and
references therein.
J. Crooks, K. O ’Malley, and I. H. Stevenson, Pharmacokinetics in
the elderly. Clin. Pharmacokinet., 7: 280 (1976).
E. J. Triggs and R. L. Nation, Pharmacokinetics in the aged. J.
Pharmacokinet. Biopharm., 5: 387 (1975).
G. Levy, ed., Clinical Pharmacokinetics, A.Ph.A., Washington,
D.C., 1974.
L. Z. Benet, ed., The Effect o f Disease States on Drug
Pharmacokinetics. A.Ph.A., Washington, D.C., 1976.
M. J. Eadie, Plasma level monitoring of anticonvulsants. Clin.
Pharmacokinet., 1: 52 (1976).
E. F. Hvidberg and M. Dam, Clinical pharmacokinetics of
anticonvulsants. Clin. Pharmacokinet., 1 : 161 (1976).
A.J. Atkinson, Individualization of anticonvulsant therapy. Med.
Clin. North Am ., 58 : 1037 (1974).
L. Lund, Effects of phenytoin in patients with epilepsy in relation to
its concentration in plasma, in Biological Effects o f Drugs in
Relation to Their Plasma Concentrations ( S. S. Davies and B.
N. C. Prichard, eds.), University Park Press, Baltimore, 1973, p.
227.
E. Martin, T. N. Tozer, L. B. Sheiner, and S. Riegelman, The
clinical pharmacokinetics of phenytoin. J. Pharmacokinet.
Biopharm., 5: 579 (1977).
A. P. Melikian, A. B. Straughn, G. W. A. Slywka, P. L. Whyatt, and
M. C. Meyer, Bioavailability of 11 phenytoin products. J.
Pharmacokinet. Biopharm., 5 : 133 (1977).
R. E. Baars, R. P. Rapp, B. Young, and D. Canafax, Phenytoin 300
mg daily-Not a dose for everyone. Drug. Intell. Clin.
Pharm, 12: 584 (1978).
FDA Drug Bulletin, 8, No. 4 Aug-Sept, 1978.
T. M. Ludden, J. P. Allen, W. A. Vatutsky, A. V. Vicuna, J. M.
Nappi, S. F. Hoffman, J. E. Wallace, D. Lalka, and J. L. McNay,
Individualization of phenytoin dosage regimens. Clin.
Pharmacol. Ther., 21: 287 (1977).
G. E. Mawer, P. W. Mullen, M. Rodgers, A.J. Robins, and S. B.
Lucas, Phenytoin dose adjustment in epileptic patients. Br. J.
Clin. Pharmacol., 1 : 163 (1974).
A. M. Gyselynck, A. Forrey, and R. Cutler, Pharmacokinetics of
gentamicin: Distribution and plasma and renal clearance. J.
Infect. Dis. Suppl., 124: 570 (1971).
J. G. Dahlgren, E. T. Anderson, and W. L. Hewitt, Gentamicin
blood levels: A guide to nephrotoxicity. Antimicrob. Agents
Chemother., 8: 58 (1975).
E. L. Goodman, J. VanGelder, R. Holmes, A. R. Hull, and J. P.
Sanford, Prospective comparative study of variable dosage and
variable frequency regimens for administration of
gentamicin. Antimicrob. Agents Chemother., 8: 434 (1975).
F. Follath, P. Spring, M. Wenk, L. Z. Benet, and L. Dettli,
Comparative pharmacokinetics of sisomicin and netilmicin in
healthy volunteers, Proc. 10th Int. Congr. Chemotherap., Vol. 2,
Zurich, 1977, p. 979.
R. Sawchuk, D. E. Zaske, R.J. Cipolle, W. A. Wargin, and R. G.
Strate, Kinetic model for gentamicin dosing with the use of
individual patient parameters. Clin. Pharmacol. Ther., 21: 362
(1977).
G. E. Schumacher, Gentamicin blood level versus time profiles of
various dosage regimens recommended for renal
impairment. Am. J. Hosp. Pharm., 33 : 299 (1975).
R. J. Sawchuk and D. E. Zaske, Pharmacokinetics of dosing
regimens which utilize multiple intravenous infusions:
Gentamicin in burn patients. J. Pharmacokinet. Biopharm., 4:
183 (1976).
D. E. Zaske, R.J. Sawchuk, D. N. Gerding, and R. G. Strate,
Increased dosage requirements of gentamicin in burn patients. J.
Trauma, 16 : 824 (1976).
J. H. Hull and F. A. Sarubbi, Gentamicin serum concentrations:
Pharmacokinetic predictions. Ann. Intern. Med., 85 : 183 (1976).
C. Bryan, Letter to the editor. Ann. Intern. Med., 8 6: 358 (1977).
D. A. Spyker and R. L. Guerrant, Gentamicin dosage. Ann. Intern.
Med., 56: 357 (1977).
J. H. Hull and F. A. Sarubbi, In comment. Ann. Intern. Med., 86:
358 (1977).
J. S. Raichlen, Calculating gentamicin doses; J. H. Hull and F. A.
Sarubbi, In comment. Ann. Intern. Med., 85: 827, 828 (1976).
C. S. Matkovic, G. J. Pazin, S. N. Schwartz, J. A. Lyon, and A. W.
Pasculle, Aminoglycoside pharmacokinetics in obesity, 18th
 Interscience Conf. Antimicrob. Ag. Chemother, Atlanta,
Abstract 387, 1978.
M. Rowland, Clinical pharmacokinetics of lidocaine, in Clinical
Pharmacokinetics ( G. Levy, ed.), A.Ph.A., Washington, D.C.,
1974, p. 53.
N. L. Benowitz and W. Meister, Clinical pharmacokinetics of
lignocaine. Clin. Pharmacokinet., 3: 177 (1978).
G. Levy, Pharmacokinetic control of theophylline therapy,
in Clinical Pharmacokinetics ( G. Levy, ed.), A.Ph.A.,
Washington, D.C., 1974, pp. 103-110.
R. I. Ogilvie, Clinical pharmacokinetics of theophylline. Clin.
Pharmacokinet., 3: 267 (1978).
L. Hendeles, M. Weinberger, and G. Johnson, Monitoring serum
theophylline levels. Clin. Pharmacokinet., 3: 294 (1978).
(a) J. W. Kern and A. G. Lipman, Rational theophylline
therapy. DrugIntell. Clin. Pharm., 11: 144 (1977); (b) M.
Weinberger, “Rational theophylline therapy”: Article contents
questioned; J. W. Kern and A. G. Lipman, Authors’ reply. Drug
Intell. Clin. Pharm., 11: 624, 625 (1977).
L. Hendeles, L. Bighley, R. H. Richardson, C. D. Hepler, and J.
Carmichael, Frequent toxicity from intravenous aminophylline
infusions in critically ill patients. Drug Intell. Clin.
Pharm., 11:12 (1977).
M. Weinberger and E. Ginchansky, Dose-dependent kinetics of
theophylline disposition in asthmatic children. J. Pediatr., 91:
820 (1977).
P. Gal, W. J. Jusko, A. M. Yurchak, and B. A. Franklin,
Theophylline disposition in obesity. Clin. Pharmacol. Ther., 23:
438 (1978).
W. J. Jusko, J. J. Schentag, J. H. Clark, M. Gardner, and A. M.
Yurchak, Enhanced biotransformation of theophylline in
marihuana and tobacco smokers. Clin. Pharmacol. Ther., 24:
406 (1978).
J. Dasta, J. M. Mirtallo, and M. Altman, Comparison of standard
and sustained-release theophylline tablets in patients with
chronic obstructive pulmonary disease. Am. J. Hosp. Pharm., 36:
613 (1979).
L. Shusted, ed., Readings in Pharmacology, Little, Brown, Boston,
1962, p. 109.
R. W. Jelliffe, A mathematical analysis of digitalis kinetics in
patients with normal and reduced renal function. Math.
Biosci., 1 : 305 (1967).
R. W. Jelliffe, J. Buell, and R. Kalaba, Reduction of digitalis
toxicity by computer-assisted glycoside dosage regimens. Ann.
Intern. Med., 77: 891 (1972).
F. I. Marcus, Current status of therapy with digoxin. Curr. Probl.
Cardiol., 3, No. 5 (1978).
W. J. Jusko, Clinical pharmacokinetics of digoxin, in Clinical
Pharmacokinetics ( G. Levy, ed.), A.Ph.A., Washington, D.C.,
1974, p. 31.
S. Waldorff and J. Buch, Serum digoxin and empiric methods in
identification of digitoxicity. Clin. Pharmacol. Ther., 23: 19
(1978).
L. Nyberg, Bioavailability of digoxin in man after oral
administration of preparations with different dissolution
rate. Acta Pharmacol. Toxicol. Suppl., 40: 3 (1977).
J. Lindenbaum, M. H. Mellow, M. O. Blackstone, V. P. Butler,
Variation in biologic availability of digoxin from four
preparations. N. Engl. J. Med., 285, 1344-1347 (1971).
D.J. Greenblatt, T. W. Smith, and J. Koch-Weser, Bioavailability of
drugs: The digoxin dilemma. Clin. Pharmacokinet., 1, 36
(1976).
D. G. Rund, J. Lindenbaum, J. F. Dobkin, V. P. Butler, and N. R.
Saha, Decreased digoxin cardioinactive-reduced metabolites
after administration as an encapsulated liquid concentrate. Clin.
Pharmacol. Ther., 34: 738 (1983).
B. F. Johnson, J. A. Bustrack, D. R. Urbach, J. H. Hull, and R.
Marwaha, Effect of metoclopramide on digoxin absorption from
tablets and capsules. Clin. Pharmacol. Ther., 36: 724 (1984).
L. B. Sheiner, B. Rosenbert, and V. V. Marathe, Estimation of
population characteristics of pharmacokinetic parameters from
routine clinical data. J. Pharmacokinet. Biopharm., 5: 445
(1977).
R. H. Reuning, R. A. Sams, R. E. Notari, Role of pharmacokinetics
in drug dosage adjustment; pharmacologic effect kinetics and
apparent volume of distribution of digoxin. Clin.
Pharmacol., 75: 127 (1973).
J. R. Koup, D. J. Greenblatt, W. J. Jusko, T. W. Smith, and J. Koch­
Weser, Pharmacokinetics of digoxin in normal subjects after
intravenous bolus and infusion doses. J. Pharmacokinet.
Biopharm., 3 : 181 (1975).
J. R. Koup, W.J. Jusko, C. M. Elwood, and R. K. Kohli, Digoxin
pharmacokinetics: Role of renal failure in dosage regimen
design. Clin. Pharmacol. Ther., 18 : 9 (1975).
W. G. Kramer, R. P. Lewis, T. C. Cobb, W. F. Forester, Jr., J. A.
Visconti, L. A. Wanke, H. G. Boxenbaum, and R. H. Reuning,
Pharmacokinetics of digoxin: Comparison of a two- and a three-
compartment model in man. J . Pharmacokinet. Biopharm., 2:
299 (1974).