Ebook Pharmacokinetics Basics To Applications Biswajit Mukherjee Online PDF All Chapter

Pharmacokinetics Basics to
Applications Biswajit Mukherjee

Visit to download the full and correct content document:
https://ebookmeta.com/product/pharmacokinetics-basics-to-applications-biswajit-muk
herjee/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...
Rowland and Tozer s Clinical Pharmacokinetics and

Pharmacodynamics Concepts and Applications Concepts and
Applications 5th Edition Derendorf
https://ebookmeta.com/product/rowland-and-tozer-s-clinical-
pharmacokinetics-and-pharmacodynamics-concepts-and-applications-
concepts-and-applications-5th-edition-derendorf/
High-Entropy Materials: From Basics to Applications 1st

Edition Huimin Xiang
https://ebookmeta.com/product/high-entropy-materials-from-basics-
to-applications-1st-edition-huimin-xiang/
Superconductivity Basics and Applications to Magnets

2nd Edition R. G. Sharma
https://ebookmeta.com/product/superconductivity-basics-and-
applications-to-magnets-2nd-edition-r-g-sharma/
Lubricants and Waxes From Basics to Applications 1st

Edition Dhananjoy Ghosh
https://ebookmeta.com/product/lubricants-and-waxes-from-basics-
to-applications-1st-edition-dhananjoy-ghosh/
Statistical Thermodynamics Basics and Applications to
Chemical Systems 1st Edition Iwao Teraoka
https://ebookmeta.com/product/statistical-thermodynamics-basics-
and-applications-to-chemical-systems-1st-edition-iwao-teraoka/
Semiconductors for Optoelectronics Basics and

Applications Naci Balkan
https://ebookmeta.com/product/semiconductors-for-optoelectronics-
basics-and-applications-naci-balkan/
Basic Pharmacokinetics, 3rd Edition Mohsen A. Hedaya
https://ebookmeta.com/product/basic-pharmacokinetics-3rd-edition-
mohsen-a-hedaya/
Handbook of Pharmacokinetics and Toxicokinetics Mehdi

Boroujerdi
https://ebookmeta.com/product/handbook-of-pharmacokinetics-and-
toxicokinetics-mehdi-boroujerdi/
Ascending Order Rohan Mukherjee
https://ebookmeta.com/product/ascending-order-rohan-mukherjee/
Biswajit Mukherjee
Pharmacokinetics:
Basics
to Applications
Pharmacokinetics: Basics to Applications
Biswajit Mukherjee
Pharmacokinetics: Basics
to Applications
Biswajit Mukherjee
Department of Pharmaceutical Technology
Jadavpur University
Kolkata, West Bengal, India
ISBN 978-981-16-8949-9 ISBN 978-981-16-8950-5 (eBook)

https://doi.org/10.1007/978-981-16-8950-5
# The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore
Pte Ltd. 2022
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by
similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or
the editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
My beloved parents, whose love, affection,
and blessings have always taught me to
possess perseverance, dedication, devotion,
and sincerity.
Preface
Pharmacokinetics: Basics to Applications is a textbook-cum-comprehensive guide-

book for students and researchers of versatile fields of pharmaceutical and biomedi-
cal sciences that deal with pharmacokinetics as a subject and its application in
research, industry, and clinical investigations. The book can be beneficial for
undergraduate, graduate, and postgraduate students of pharmacy, pharmaceutical
sciences, pharmaceutical technology, clinical pharmacy, pharmacy practice, medi-
cine, faculties of the fields, researchers/scientists of pharmaceutical industries, and
persons engaged in clinical investigations. I have initially introduced pharmacoki-
netics, followed by the idea of different pharmacokinetic parameters and the funda-
mental pharmacokinetic phenomena—absorption, distribution, metabolism, and
elimination (ADME), including nonlinear kinetics. The explicit knowledge of the
extent of drug absorption, bioavailability, clearance, bioequivalence, and protein
binding, pharmacokinetic drug–drug interactions are also the parts of the book
content. I have also explained the application of the subject in preclinical and clinical
study designing and experiments. Right from the sample collection to its analysis,
statistical data analysis guidelines, and the awareness of pharmacokinetic software
have been included in the book. Various up-to-date pharmacokinetic experiments
and the procedure of seeking clinical approval and clinical data collections have
been included to provide real-time ideas and knowledge of the subject to make
students well equipped to be true pharmacokinetic professionals. Finally, numerical
problems and questions and answers have been incorporated to assist students in
understanding and practicing the critical aspects of the chapters for examinations.
My primary intention in writing the book is to present a complex subject in one
easy way by sharing a vast more than 25 years of university-level teaching and
research experience in the field. In its originality, the book can guide its readers
through the sequential steps of learning pharmacokinetics quickly in a lucid lan-
guage. I have always given the substantial effort and minute care to avoid unneces-
sarily making it complex to the readers. Adequate and requisite information has been
included in the book. All the equations are vividly described without missing or
jumping any steps. It would definitely help the beginners to the subject to understand
and learn pharmacokinetics quite easily. This book has lots of illustrations, a few
photographs, and necessary tables that further build the deep foundation and better
clarification of the subject to a reader. All the figures have been self-drawn by the
author alone so that the correct intended message through the illustrations can
vii
viii Preface
nourish the inquisitive minds of the readers. A few unpublished photographs have
also been incorporated. It took little more than 8670 h to complete the book. I typed
the entire book materials by myself to avoid mistakes or minimize the number of
mistakes significantly. The information is being shared to clarify my dedication,
devotion, and efforts instilled in the book to inculcate the knowledge of the subject
with an easy presentation in pupils. I wrote the book based on the classical and
pioneering work and some significant current reports to balance and finely tune the
knowledge. Since it is a textbook, priority has been given to the established, well-
accepted knowledge. Necessary fundamental mathematics and statistics for easy and
faster deduction and understanding of the equations have been incorporated in the
book. The single book would guide the students in all necessary learning related to
better assimilating the subject knowledge without additional support.
I sincerely thank all the researchers who have enriched the field, particularly those
whose publications have been considered in writing the book. Of course, without the
support of my family members, it could have been impossible for me to write this
book. Finally, I believe that this explicitly presented knowledge of pharmacokinetics
will help the students acquire the foundation of pharmacokinetics and the growth of
the subject knowledge and its applications in the field.
Kolkata, India Biswajit Mukherjee

Acknowledgment
To my beloved wife, and lovely son and daughter for their endless love, support, and
encouragement, without which it would be hard for me to complete the book
ix
Contents
1 Fundamentals of Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Fundamentals of Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Pharmacokinetic Parameters and Blood Drug
Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.1.2 Multiple-Dose Regimen . . . . . . . . . . . . . . . . . . . . . . 7
1.1.3 Apparent Volume of Distribution or Volume of
Distribution (vd) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.1.4 Steady-State Plasma Concentration of Drug . . . . . . . . 12
1.1.5 Drug Accumulation Factor . . . . . . . . . . . . . . . . . . . . 15
1.1.6 Krüger-Thiemer’s “Pharmacokinetic Factor” . . . . . . . 17
1.1.7 Krüger-Thiemer Dose Ratio . . . . . . . . . . . . . . . . . . . 17
1.1.8 Concept of a Loading Dose . . . . . . . . . . . . . . . . . . . . 18
1.1.9 Relationship Between Elimination Rate Constant
(KE) and Steady-State Drug Plasma Concentration
(css) from Krüger-Thiemer Dose Ratio Concept . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2 Drug Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1 Drug Absorption and Determination of Drug Absorption
Rate Constant “Ka” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1.1 Dominguez Equation and Its Importance . . . . . . . . . . 22
2.1.2 Wagner–Nelson Equation and Method
of Determination of Drug Absorption Rate
Constant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1.3 Determination of Absorption Rate Constant
(Ka) from Urinary Excretion Data . . . . . . . . . . . . . . . 25
2.1.4 Nelson Equation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.1.5 Wagner and Nelson Equation . . . . . . . . . . . . . . . . . . 27
2.1.6 Loo–Riegelman Method for Determination
of Drug Absorption Rate (Ka) . . . . . . . . . . . . . . . . . . 28
xi
xii Contents
2.1.7 Method of Residual for Determination

of Drug Absorption Rate . . . . . . . . . . . . . . . . . . . . . . 31
2.1.8 Flip-Flop Phenomenon . . . . . . . . . . . . . . . . . . . . . . . 32
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3 Extent of Drug Absorption: Bioavailability, Clearance,
Bioequivalence, and Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . 37
3.1 Extent of Drug Absorption: Bioavailability . . . . . . . . . . . . . . . . 37
3.1.1 Renal Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.1.2 Determination of Absolute Bioavailability . . . . . . . . . 39
3.1.3 Determination of Absolute Bioavailability
by Urinary Excretion Data . . . . . . . . . . . . . . . . . . . . 41
3.1.4 Bioequivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.1.5 Drug–Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . 45
3.1.6 Reciprocal Plot or Klotz Reciprocal Plot . . . . . . . . . . 46
3.1.7 Scatchard Plot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.1.8 Sandberg Plot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4 Pharmacokinetic Models and Drug Distribution . . . . . . . . . . . . . . . 51
4.1 Various Pharmacokinetic Models and Drug Distribution . . . . . . 51
4.1.1 Physiological Pharmacokinetic Model
(Flow Model) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.1.2 Blood Flow–Limited Physiological Pharmacokinetic
Model or Perfusion Model . . . . . . . . . . . . . . . . . . . . 54
4.1.3 Physiological Pharmacokinetic Model with
Drug–Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . 58
4.1.4 Membrane-Limited Model or Diffusion-Limited
Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.1.5 Statistical Moment Theory . . . . . . . . . . . . . . . . . . . . 60
4.1.6 Compartment Models . . . . . . . . . . . . . . . . . . . . . . . . 61
4.1.7 Some Mathematical Approaches for Easy
Computation of Compartmental Equations
and Their Applications . . . . . . . . . . . . . . . . . . . . . . . 63
4.1.8 Details About Compartment Models . . . . . . . . . . . . . 84
4.1.9 Drug Distribution Study Through Compartmental
Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5 Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.1 Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.1.1 Hepatic Drug Metabolism . . . . . . . . . . . . . . . . . . . . . 111
5.1.2 Pharmacokinetic Compartmental Models
and Equations for Assessing Hepatic “First-Pass”
Effect of a Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.1.3 Hepatic First-Pass Effect Invariably Reduces
Total Bioavailability of a Drug More When
Administered Orally than By Its Intravenous Route
of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Contents xiii
5.1.4 Determination of Drug Metabolite Levels in Plasma

Using Compartmental Model . . . . . . . . . . . . . . . . . . . 120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
6 Drug Elimination and Nonlinear Kinetics . . . . . . . . . . . . . . . . . . . . 125
6.1 Drug Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
6.1.1 Nonlinear Kinetics and Capacity-Limited Process . . . . 125
6.1.2 Michaelis–Menten Equation . . . . . . . . . . . . . . . . . . . 125
6.1.3 Capacity-Limited Process/Nonlinear Kinetics . . . . . . . 129
6.1.4 Dose–Plasma Drug Concentration Relationship
with Michaelis–Menten Constant Km for Drugs
That Undergo Elimination Following
Michaelis–Menten Nonlinear Kinetics . . . . . . . . . . . . 131
6.1.5 Drug Elimination by More Than One
Capacity-Limited Process . . . . . . . . . . . . . . . . . . . . . 132
6.1.6 Sigma-Minus Method to Determine Elimination
Rate Constant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
6.1.7 Bi-Exponential Absorption–Elimination Equation
for Orally Administered Drugs Excreted Unchanged
Through Urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
6.1.8 Excretion Rate Method . . . . . . . . . . . . . . . . . . . . . . . 142
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
7 Pharmacokinetic Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . 145
7.1 Pharmacokinetic Drug–Drug Interactions . . . . . . . . . . . . . . . . . 145
7.1.1 Importance of Drug–Drug Interactions . . . . . . . . . . . . 145
7.1.2 Categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
7.1.3 Drug–Drug Interactions: Pharmacokinetic Type . . . . . 150
7.1.4 Drug–Drug Interactions: Pharmacodynamic Type . . . . 152
7.1.5 Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
8 Pharmacokinetic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
8.1 Therapeutic Drug Monitoring and Dose Formula . . . . . . . . . . . . 157
8.1.1 Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . 157
8.1.2 Physiological Effects on the Pharmacokinetic
Drug Parameters and Available Dose Formula in
Neonates, Infants, Children, Elderly Patients, Obese
Patients, and Patients with Liver and Kidney
Insufficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Parameters of Drugs and Available Dose Formula
in Elderly or Geriatric Patients . . . . . . . . . . . . . . . . . . 161
Parameters of Drugs in Obese Patients . . . . . . . . . . . . 163
xiv Contents

Parameters of Drugs and Available Dose Formula
in Patients with Renal Insufficiency . . . . . . . . . . . . . . 163
8.1.6 Chronological Pharmacokinetic Guidance for
Preclinical and Clinical Studies and Research . . . . . . . 164
8.1.7 Analysis of Pharmacokinetic Data . . . . . . . . . . . . . . . 169
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
9 Pharmacokinetic Sample Collection and Processing . . . . . . . . . . . . 175
9.1 Pharmacokinetic Sample Collection and Processing
for Preclinical and Clinical Experiments . . . . . . . . . . . . . . . . . . 175
9.1.1 Pharmacokinetic Sampling . . . . . . . . . . . . . . . . . . . . 175
9.1.2 Blood Sampling and Right Practices
in Phlebotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
9.1.3 Urine Specimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
9.1.4 Other Tissue Samples . . . . . . . . . . . . . . . . . . . . . . . . 179
9.1.5 Other Tissue Fluids . . . . . . . . . . . . . . . . . . . . . . . . . 181
9.1.6 Processing of Fecal Samples . . . . . . . . . . . . . . . . . . . 181
9.1.7 Extraction of Drug/Drug Metabolite from
Biological Samples . . . . . . . . . . . . . . . . . . . . . . . . . . 182
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10 Important Bioanalytical Instrumental Techniques in
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
10.1 Important Bioanalytical Instrumental Techniques . . . . . . . . . . . 185
10.1.1 Liquid Chromatography with Tandem Mass
Spectroscopy (LC-MS/MS) . . . . . . . . . . . . . . . . . . . . 185
10.1.2 High-Performance Liquid Chromatography
(HPLC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
11 Statistics in Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
11.1 Statistics and Biometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
11.1.1 Central Tendency . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
11.1.2 Measure of Dispersion . . . . . . . . . . . . . . . . . . . . . . . 203
11.1.3 Probability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
11.1.4 Some Important Definitions . . . . . . . . . . . . . . . . . . . . 208
11.1.5 The Null Hypothesis, Alternate Hypothesis,
and Degree of Freedom . . . . . . . . . . . . . . . . . . . . . . . 210
11.1.6 Population and Sample . . . . . . . . . . . . . . . . . . . . . . . 210
11.1.7 Selection of Statistical Methods . . . . . . . . . . . . . . . . . 211
11.1.8 Different Statistical Methods Used in
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
11.1.9 Scattergram, Linear Regression Model, Correlation
Coefficient, Nonlinear Regression Model . . . . . . . . . . 224
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Contents xv
12 Pharmacokinetic Software and Tools . . . . . . . . . . . . . . . . . . . . . . . 227

12.1 Pharmacokinetic Software and Tools . . . . . . . . . . . . . . . . . . . . 227
12.1.1 Software and Tools . . . . . . . . . . . . . . . . . . . . . . . . . . 227
12.1.2 Types of Software . . . . . . . . . . . . . . . . . . . . . . . . . . 227
12.1.3 Importance of Pharmacokinetic Software . . . . . . . . . . 228
12.1.4 Open Source and Commercial Pharmacokinetic
Software and Tools . . . . . . . . . . . . . . . . . . . . . . . . . . 228
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
13 Pharmacokinetic Laboratory-Based Experiments . . . . . . . . . . . . . . 233
13.1 Pharmacokinetic Laboratory-Based Experiments for
Undergraduate and Postgraduate Students . . . . . . . . . . . . . . . . . 233
13.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
13.1.2 Helpful Information in Laboratory Work . . . . . . . . . . 234
13.1.3 Drug-Plasma Protein (Albumin)-Binding
Assessment with a Low Plasma Protein Binding
Drug or a High Plasma Protein Binding Drug . . . . . . . 237
13.1.4 Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
13.1.5 One-Compartment Model Following an Intravenous
Bolus Dose Administration . . . . . . . . . . . . . . . . . . . . 248
13.1.6 One-Compartment Model Following an Intravenous
Infusion Administration . . . . . . . . . . . . . . . . . . . . . . 251
13.1.7 A Two-Compartment Model Following the
Administration of an Intravenous Bolus Dose . . . . . . . 253
13.1.8 A Multi(Three)-Compartment Model Following the
Administration of an Intravenous Infusion . . . . . . . . . 255
13.1.9 Determination of Drug Absorption In Vitro . . . . . . . . 258
13.1.10 Cellular Uptake of Drug . . . . . . . . . . . . . . . . . . . . . . 260
13.1.11 In Vitro Drug Skin Permeation from Transdermal
Drug Delivery System (Patch) . . . . . . . . . . . . . . . . . . 263
13.1.12 Drug Assay from a Tablet Dosage Form Containing
Paracetamol by HPLC Method . . . . . . . . . . . . . . . . . 265
13.1.13 Estimation of Plasma and Urine Drug
Concentrations by Reversed-Phase HPLC . . . . . . . . . 267
13.1.14 Compare the Bioavailability of Ranitidine (300 mg)
Tablets of Two Different Brands in Human
Volunteers (Bioequivalence Study) . . . . . . . . . . . . . . 269
13.1.15 Effect of Food Intake on Drug Bioavailability . . . . . . 270
13.1.16 The Metabolism of Oxybutynin Hydrochloride
to Its Metabolite N-Desethyl Oxybutynin
Hydrochloride by Rat Liver Microsomes . . . . . . . . . . 272
13.1.17 Simultaneous Determination of Drugs Spiked into
Plasma from a Single Tablet Dosage,
Using LC-MS System . . . . . . . . . . . . . . . . . . . . . . . . 274
xvi Contents
13.1.18 Determination of Metformin and Canagliflozin

from a Single Tablet Dosage in Human Plasma
by LC-MS/MS Method . . . . . . . . . . . . . . . . . . . . . . . 276
13.1.19 Retrospective Data Collection . . . . . . . . . . . . . . . . . . 279
13.1.20 Development of Clinical Trial Protocol . . . . . . . . . . . 279
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
14 Pharmacokinetic Numerical Problems with Solutions . . . . . . . . . . . 287
15 Questions, and Questions and Answers for Practice . . . . . . . . . . . . 307
15.1 The Practice of Questions and Answers on Topics Based
on Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
15.2 Multiple Choice Questions with Answers for Various
Competitive Examinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
15.3 Selected Questions from the University Examinations . . . . . . . . 321
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
About the Author
Biswajit Mukherjee PhD, WBCS, FIC, FICS, is a Professor and former Head
in the Department of Pharmaceutical Technology, Jadavpur University, Kolkata,
India and a former faculty of the University Institute of Pharmaceutical Sciences,
Panjab University, Chandigarh. He was a DAAD (German Academic Exchange
Services) Fellow and Guest Scientist, German Cancer Research Center (DKFZ),
Heidelberg. He was a visiting fellow of the School of Pharmacy, University of
London, and an Indo-Hungarian Education Exchange Fellow, of the National
Research Institute for Radiobiology and Radiohygiene, Budapest. He works on
antisense technology, nanomedicine, and targeted drug delivery on pharmacokinetics
and pharmacodynamics.
xvii
List of Figures
Fig. 1.1 The figure shows plasma drug concentration versus time curve
that demonstrates how a drug behaves in the blood after its
absorption upon a single-dose administration by any routes other
than an intravenous route for systemic drug action. Various
pharmacokinetic parameters of the drug in the blood are also
seen. The Cmax is the maximum plasma drug concentration at
Tmax (time taken to reach Cmax). The MEC is the minimum
effective drug concentration to begin therapeutic drug action.
The MTC is the minimum toxic drug concentration, and it is also
known as the maximum safe drug concentration or the MSC. The
plasma drug concentration between the MEC and the MTC is
called the therapeutic window. After a drug administration by
oral route or by any routes other than intravenous route, the time
point at which the drug reaches minimum therapeutically effec-
tive drug concentration implies the onset of drug action . . . . . . . . . . . 2
Fig. 1.2 The figure shows plasma drug concentration versus time curve
that shows how a drug behaves after its single-dose administra-
tion by intravenous route. The MEC is the minimum effective
drug concentration to begin therapeutic drug action. The MTC is
the minimum toxic drug concentration, and it is also known as
the maximum safe drug concentration or the MSC . . . . . . . . . . . . . . . . . 4
Fig. 1.3 In a multiple-dose (repeated-dose) regimen for oral/any routes
other than the intravenous route of drug administration for sys-
temic drug action, plasma drug concentration versus time curve
for the first dose and subsequent doses show peak and valley
appearance between the minimum effective drug concentration
(MEC) and the minimum toxic drug concentration (MTC) levels
in the blood. The maximum plasma concentration (Cmax) and
time to achieve Cmax (Tmax) are shown after the first dose in the
drug absorption curve. Every individual peak represents the
Cmax after each dose at the respective Tmax . . . . . . . . . . . . . . . . . . . . . . . 8
xix
xx List of Figures
Fig. 1.4 In a multiple-dose (repeated-dose) regimen of the intravenous

route of drug administration, plasma drug concentration versus
time curve for the first dose and subsequent doses shows peak
and valley appearance between the minimum effective drug
concentration (MEC) and the maximum safe drug concentration
(MSC) levels in the blood . . . .. . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . . 8
Fig. 1.5 The plasma drug concentration versus time curve upon drug
administration by oral route/any route other than the intravenous
route for systemic drug action shows that in each of the
subsequent doses, the maximum and minimum plasma drug
concentration values increase during drug absorption at the ini-
tial phase. After administering several doses, the maximum and
minimum plasma drug concentration values become constant.
The average plasma drug concentration at the zone is called
steady-state plasma drug concentration (css). At the steady state,
the maximum constant plasma drug concentration value is called
steady-state maximum plasma drug concentration (css)max.
Likewise, the minimum constant plasma drug concentration
value is called the steady-state minimum plasma drug concen-
tration (css)min. MEC indicates minimum effective drug concen-
tration, MTC denotes minimum toxic drug concentration . . . . . . . . 13
Fig. 1.6 The plasma drug concentration versus time curve upon drug
administration by intravenous route shows that the maximum
and minimum drug plasma concentration values increase upon
drug administration at the initial phase in each of the subsequent
doses. After administering many doses, the maximum and min-
imum plasma drug concentration values become constant. The
average plasma drug concentration at the region is called steady-
state plasma concentration (css). At the steady state, the maxi-
mum constant plasma drug concentration value is called steady-
state maximum plasma drug concentration (css)max, and the
minimum constant plasma drug concentration value is called the
steady-state minimum plasma drug concentration (css)min. MEC
indicates minimum effective drug concentration, MTC denotes
minimum toxic drug concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Fig. 2.1 Plasma drug concentration versus time curve after the drug
absorption following a single dose by oral route/any routes other
than the intravenous route of drug administration for systemic
drug action. The area under the curve, shown by stars and
RT
depicted by 0 cp dt, shows bioavailability of the drug during the
period of 0–T, after its administration. MEC indicates minimum
effective drug concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
List of Figures xxi
Fig. 2.2 Plasma drug concentration versus time curve after drug absorp-
tion following a single dose by oral route/any routes other than
the intravenous route of drug administration for systemic drug
action.
R1 The area under the curve, shown by stars and depicted by
0 c p dt, shows the total bioavailability of the drug. MEC
indicates minimum effective drug concentration . . . . . . . . . . . . . . . . . . 24
Fig. 2.3 Percentage of drug remaining to be absorbed when plotted
against time on a semi-log paper, keeping “percentage of drug
remaining to be absorbed” on a log scale and time on a linear
K a
scale, gives a straight line. The slope of the line is 2:303 where Ka
provides the value of absorption rate constant . . . . . . . . . . . . . . . . . . . . . 25
K a
K a
Fig. 2.6 The figure shows the residual plot of the plasma drug absorption
curve following the oral route of a single-dose drug administra-
tion. Plasma drug concentrations on the curve provide the actual
drug absorption data (shown by “actual drug concentration”).
The post absorption terminal linear portion down the curve when
extrapolated to the plasma drug concentration axis (y-axis), the
data on the line provide the extrapolated drug concentrations.
The difference between the extrapolated drug concentration and
the actual drug concentration gives the value of residual drug
concentration (CR). When log CR is plotted against time, the
K a
slope of the line provides the value of 2:303 , where Ka is drug
absorption rate. The “vs.” stands for “versus” . . . . . . . . . . . . . . . . . . . . . 31
Fig. 2.7 The figure shows that the extrapolated line and the feathered
K a
(residual) line with a slope 2:303 of the plot provide negative lag
time. The meeting point of the extrapolated line and the residual
line gives the value of lag time t0. In the graph, a negative lag
time (which indicates erroneous findings) is shown. Here, loga-
rithm values of residual drug concentration logcR are plotted
against time t . .. . . .. . . . .. . . .. . . .. . . .. . . . .. . . .. . . .. . . .. . . . .. . . .. . . .. . . . . 33
Fig. 2.8 Residual plot of extravascular drug administration. Logarithm
plasma concentration, logcp, data plotted against time that shows
the slope of the terminal linear portion of the line provides the
xxii List of Figures
K a
value of 2:303 where Ka is the rate of drug absorption. The slope of
K E
the feathered line gives the value of 2:303 where KE is the rate of
elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Fig. 2.9 Residual plot of intravascular drug administration. Logarithm
plasma concentration, logcp, data plotted against time that shows
the slope of the terminal linear portion of the line provides the
K a
value of 2:303 where Ka is the rate of drug absorption. The slope of
K E
the feathered line gives the value of 2:303 where KE is the rate of
elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Fig. 3.1 The figure shows Klotz reciprocal plot for the quantification for
protein–drug binding. The data of 1r (where r is the ratio of
protein-bound drug to total protein) are plotted against ½D1 (where
[D] is the molar concentration of free drug in plasma), and the
1
slope of the line gives the value of νK . The extrapolated line gives
the value of the intercept ν on r -axis (y-axis). Here, “ν” is the
1 1
number of binding sites of a protein molecule for drug

molecules, and “K” is the equilibrium rate constant . . . . . . . . . . . . . . . 47
Fig. 3.2 The figure shows a Scatchard plot for the quantification for
protein–drug binding. Data of ½Dr (where r is the ratio of protein-
bound drug to total protein and [D] is the molar plasma free drug
concentration) are plotted against r, and the slope of the line
gives the value of K. The intercept of the line provides the value
with νK on ½Dr -axis (y-axis). Here, “ν” is the number of binding
sites of a protein molecule for drug molecules, and “K” is the
equilibrium rate constant . . .. . . .. . . . .. . . .. . . .. . . .. . . .. . . .. . . .. . . .. . . .. 48
Fig. 3.3 The figure shows the Sandberg plot for the quantification for
protein–drug binding. Data of D b
Df (where Db is the concentration
of the protein-bound drug and Df is the free drug concentration)
are plotted against Db, and the slope of the line gives the value of
K. The intercept of the line provides the value with νK[Pt]
“ ”
on DDf -axis (y-axis). Here, ν is the number of binding sites of a
b
protein molecule for drug molecules. “K” is the equilibrium rate

constant and [Pt] is the concentration of the total protein . . . . . . . . . 49
Fig. 4.1 The figure shows a physiological pharmacokinetic model of drug
transportation to the extracellular fluid by blood capillaries
connected to the arterioles, and drug molecules/drug metabolites
that diffuse out of the cells to the extracellular fluid are
transported back to the venules for removal . . . . . . . . . . . . . . . . . . . . . . . 52
Fig. 4.2 The figure shows a physiological pharmacokinetic model of drug
elimination: (A) After the drug transportation to the extracellular
fluid by blood capillaries connected to arterioles, the drug
List of Figures xxiii
diffuses into the cells, and drug molecules/drug metabolites that

diffuse out of the cells to the extracellular fluid are transported
back to the venules to venous blood for elimination. (B) After the
drug transportation to the extracellular fluid by blood capillaries
connected to arterioles, the drug diffuses into the cells, and drug
molecules/drug metabolites diffuse out of the cells to the extra-
cellular fluid from where the drug is eliminated through
the organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Fig. 4.3 The figure shows that in a flow-limited physiological model,
drug distribution from the arterial blood to different tissues for
drug absorption, and then from the tissues, the drug molecules/
drug metabolites diffuse out to the vein. The rate of drug
dðcp vd Þ
dt is quantified by dt ¼
dx
absorption dx dt , where cp is the
plasma drug concentration and vd is the volume of distribution.
However, the rate of blood flow from the tissue to the venous
dQ
blood is tissue specific and quantified by dttissue . GIT denotes
gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Fig. 4.4 The figure depicts reversible drug–protein binding phenomena in
the blood and the tissue and the exchange of drugs between those
tissues . . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. . .. .. 58
Fig. 4.5 One-compartment closed model that shows x0 amount of drug is
administered to an entirely homogeneous body compartment . . . . 61
Fig. 4.6 One-compartment open model that shows x0 amount of drug is
administered to an entirely homogeneous body compartment,
and the drug is eliminated from it. k10 indicates the rate of drug
elimination, and the arrowhead indicates the drug is eliminated
outside the body compartment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Fig. 4.7 The figure shows a catenary model where all the compartments
are connected like the compartments of a train . . . . . . . . . . . . . . . . . . . . 62
Fig. 4.8 The figure shows a cyclic model. It is like a catenary model
where two terminal compartments are connected to each other to
form a closed structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Fig. 4.9 The figure shows a mammillary model where all the
compartments are connected to a central compartment . . . . . . . . . . . 63
Fig. 4.10 One-compartment open model that shows x0 amount of drug is
administered intravenously at the time t0 to an entirely homoge-
neous body compartment, xB is the amount of drug present in the
compartment at time t, and the drug is eliminated from it. KE
indicates the rate of drug elimination, and the arrowhead
indicates the drug is eliminated outside the body compartment . . 86
Fig. 4.11 Plot of logarithmic plasma drug concentration ( log cp) versus
time on a semi-logarithmic paper. The slope of the line gives us
2:303
KE
and the intercept on the y-axis of the extrapolated line
gives us logc0 where c0 is the instantaneous plasma drug con-
centration upon the administration of x0 amount of drug . . . . . . . . . 88
xxiv List of Figures
Fig. 4.12 The figure shows a one-compartment open model where a drug is
administered by infusion at a rate k0. KE is the rate of drug
elimination from the compartment and xB is the amount of drug
present in the compartment at time t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Fig. 4.13 Plot of logarithmic plasma drug concentration versus time of a
patient who received intravenous drug infusion and achieved the
steady-state plasma drug level. Then, the infusion was stopped at
time T. The time t0 elapsed after the stop of the drug infusion in
the patient at time T. The time t is the total time the patient was
supposed to receive the infusion and had steady-state plasma
drug concentration. The dotted line shows the drop of plasma
drug concentration after the stop of the infusion . . . . . . . . . . . . . . . . . . 90
Fig. 4.14 Plot of logarithmic plasma drug concentration versus time of a
patient who receives intravenous drug infusion and should
achieve the steady-state plasma drug level at time t, and any
duration of time t0 before achieving the steady-state plasma drug
concentration, the drug infusion is stopped for the patient at time
T. The dotted line shows the drop of plasma drug concentration
after the stop of the infusion . . .. . . . .. . . . . .. . . . .. . . . .. . . . . .. . . . .. . . . .. 92
Fig. 4.15 Two-compartment open models. Model I: x0 is the dose
administered by the intravenous route to the central compartment
and xc is the amount of drug present at the central compartment
(compartment “1”) at time t and xp is the amount of drug present
at the peripheral compartment (here designated as compartment
“2”) at time t. Further, the drug is eliminated from the central
compartment. Model II: xc is considered as the amount of drug
present at the central compartment (compartment “1”) at time
t and xp is the amount of drug present at the peripheral com-
partment (here designated as compartment “2”) at time t. x0 is the
dose administered by intravenous injection into the blood (cen-
tral compartment). Further, the drug is eliminated from both the
central compartment and the peripheral compartment. Model III:
x0 is the dose administered by the intravenous route to the central
compartment and xc is the amount of drug present at the central
compartment (compartment “1”) at time t and xp is the amount of
drug present at the peripheral compartment (here designated as
compartment “2”) at time t. Further, the drug is eliminated from
the peripheral compartment. In all the models, K12, K21, K10, and
K20 are the respective rate constants, and each arrowhead shows
the direction of movement of the drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Fig. 4.16 The figure shows the changes of logarithmic drug amount against
time in the blood compartment (central compartment) and the
tissue compartment (peripheral compartment) following a
two-compartment model when the drug is administered by
List of Figures xxv
intravenous route in a patient. Data show that the drug avail-

ability is more in the central compartment compared to the tissue
compartment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Fig. 4.17 The figure shows the changes of logarithmic drug amount
against time in the blood compartment (central compartment)
and the tissue compartment (peripheral compartment) following
a two-compartment model when the drug is administered by
intravenous route in a patient. Data show that the drug avail-
ability is more in the peripheral (tissue) compartment compared
to the central compartment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Fig. 4.18 Plot of logarithmic tissue drug amount against the time of a
two-compartment model. The slope of the line gives us the
value of β, and the intercept of the extrapolated line gives us
log x0 K 12
αβ , where α is the drug absorption rate, β is the drug
elimination rate, x0 is the dose, and K12 is the rate of drug
transport from the central compartment to the peripheral
compartment . . . .. . . . .. . . . . .. . . . .. . . . .. . . . .. . . . . .. . . . .. . . . .. . . . . .. . . . . 101
Fig. 4.19 Three-compartment open models. Model I: Where x0 is the
amount of drug administered by the intravenous route to the
central compartment and xc is the amount of drug present at the
central compartment (compartment “1”) at time t and xp and xq
are the amounts of drug present at the two peripheral
compartments (here designated as compartment “2” and “3,”
respectively) at time t. Further, the drug is eliminated from the
central compartment. Model II: Where x0 is the
central compartment and the peripheral compartment number 3.
Model III: Where x0 is the amount of drug administered by the
intravenous route to the central compartment and xc is the
amount of drug present at the central compartment (compartment
“1”) at time t and xp and xq are the amounts of drug present at the
two peripheral compartments (here designated as compartment
“2” and “3,” respectively) at time t. Further, the drug is
eliminated from the central compartment and peripheral
compartments, numbers 2 and 3. Model IV: Where x0 is the
xxvi List of Figures

central compartment and the peripheral compartment number 2.
Model V: Where x0 is the amount of drug administered by the
intravenous route to the central compartment and xc is the
amount of drug present at the central compartment (compartment
“1”) at time t and xp and xq are the amounts of drug present at the
two peripheral compartments (here designated as compartment
“2” and “3,” respectively) at time t. Further, the drug is
eliminated from peripheral compartment number 2. Model VI:
Where x0 is the amount of drug administered by the intravenous
route to the central compartment and xc is the amount of drug
present at the central compartment (compartment “1”) at time
t and xp and xq are the amounts of drug present at the two
peripheral compartments (here designated as compartment “2”
and “3,” respectively) at time t. Further, the drug is eliminated
from peripheral compartment number 3. In all the models, K12,
K21, K13, K31, K10, K20, and K30 are the respective rate constants,
and each arrowhead shows the direction of movement of the
drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Fig. 5.1 Two-compartment model to investigate and compare the hepatic
first-pass effect of drug administered by different routes. The
self-explanatory model shows drug absorption and drug elimi-
nation from various compartments as explained under 5.1.2.1–
5.1.2.4 .. . . . . .. . . . . .. . . . . .. . . . . . .. . . . . .. . . . . .. . . . . .. . . . . . .. . . . . .. . . . . .. 114
Fig. 5.2 The x0 amount of drug has been administered in the central
compartment. xB is the amount of drug and MB is the amount of
drug metabolite present in the central compartment (compart-
ment “1”) at time t. Mu is the amount of drug metabolite
eliminated through urine at time t. Kf, and Km are the respective
rate constants of drug to metabolite conversion and the elimina-
tion of drug metabolite through the urine. Each arrowhead shows
the direction of the movement of the drug metabolite . . . . . . . . . . . 121
Fig. 5.3 Plot of logarithmic plasma drug metabolite concentration
(logcm) versus time on a semi-logarithmic paper. The slope of
the line gives us 2:303 KE
and the intercept on the y-axis of the
extrapolated line gives us log vm ðKKmf xK 0
EÞ
where Kf and Km are
the respective rate constants of drug to metabolite conversion
and the elimination of drug metabolite through the urine. KE is
the drug elimination rate, and vm is the volume of distribution
of the drug metabolite upon the administration of x0 amount of
drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
List of Figures xxvii
Fig. 5.4 Plot of logarithmic plasma drug metabolite concentration

(logcm) versus time on a semi-logarithmic paper. The slope of
the line gives us 2:303
Km
and the intercept on the y-axis of the
extrapolated line gives us log vm ðKKEf K
x0
mÞ
where Kf is the rate of
drug to metabolite conversion and Km is the elimination rate of
drug metabolite through the urine. KE is the drug elimination
rate, and vm is the volume of distribution of the drug metabolite
upon the administration of x0 amount of drug . . . . . . . . . . . . . . . . . . . . 124
Fig. 6.1 A typical nonlinear kinetic plot is shown. The rate of reaction
(v) is plotted against the concentration of substrate (c) (here drug)
in an enzyme reaction. The first part of the curve shows a
concentration-dependent first-order kinetic pattern that is
followed by a zero-order kinetic pattern shown by a straight line
parallel to the x-axis (concentration axis) when the enzymes are
saturated with the substrates. The vmax is the maximum rate of
reaction .. . .. .. . .. . .. .. . .. . .. .. . .. . .. .. . .. . .. .. . .. . .. .. . .. . .. .. . .. . .. .. 126
Fig. 6.2 The figure shows the rate of drug elimination is proportionally
increased with the increase in drug concentration in the blood.
The graph represents a linear plot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Fig. 6.3 Nonlinear kinetic “Michaelis–Menten” equation when
rearranged and plotted as 1v against 1c gives a straight line. The
slope of the line shows the value of vKm max
. It is called the
Lineweaver–Burk double reciprocal plot. Here, v is the rate of
reaction, c is the concentration of substrate (here drug) in an
enzyme reaction. The vmax is the maximum rate of reaction . . . . 128
rearranged and plotted as cv against c gives a straight line. The
1
slope of the line shows the value of vmax . Here, v is the rate of
reaction, and c is the concentration of substrate (here drug) in
an enzyme reaction. The vmax is the maximum rate of reaction.
The Km is the Michaelis–Menten constant . . . . . . . . . . . . . . . . . . . . . . . . 128
rearranged and plotted as v against vc gives a straight line. The
slope of the line shows the value of km. Here, v is the reaction
rate, and c is the concentration of substrate (here drug) in an
enzyme reaction. The Km is the Michaelis–Menten constant . . . 129
rearranged and plotted as logc against t gives a straight line.
The slope of the line shows the value of 2:303 vmax
k m . Here, c is the
substrate concentration (here drug) in an enzyme reaction. The
vmax is the maximum rate of reaction. The Km is the Michaelis–
Menten constant .. . . . . . .. . . . . .. . . . . .. . . . . .. . . . . . .. . . . . .. . . . . .. . . . . .. . 131
xxviii List of Figures

Fig. 6.7 In the sigma-minus method, when log x1 u xu is plotted
against time on a semi-log paper, keeping “ log x1 u xu ” on a
log scale and time on a linear scale, it gives a straight line. The
slope of the line is 2:303 kE
where kE provides the value of
elimination rate constant. When the feathered line is drawn, the
slope of it gives the value of 2:303 Ka
where Ka is the absorption
rate constant. The total unchanged drug to be eliminated through
urine is x1u and the unchanged drug eliminated through urine at
any time t is xu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Fig. 6.8 The figure shows drug (xu) is excreted unchanged through urine
with drug elimination rate (ke) following orally administered
drug in a one-compartment model. Here, xA amount of drug is
absorbed to the central compartment from the orally
administered x0 amount of drug at an absorption rate ka at time
t and xB is the amount of drug present at the central compartment
at time t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Δx
Fig. 6.9 Plot of logarithmic values of rate, logð Δtu Þ, of drug (xu) excreted
unchanged through urine versus time on a semi-logarithmic
paper. The slope of the line gives us 2:303
e k
and the intercept on
k k Fx
the y-axis of the extrapolated line gives us log ðKa K
e 0
Þ where ka a e
is the absorption rate of drug, ke is the elimination rate of drug
excreted unchanged through urine, and F is the dose fraction
drug absorbed upon the administration of x0 amount of drug . . . 143
Fig. 9.1 Blood draw from antecubital fossa (elbow pit of the forearm) . . 177
Fig. 9.2 Urine collection funnel system for laboratory animals . . . . . . . . . . 180
Fig. 10.1 LC-MS/MS system along with its various components . . . . . . . . . 186
Fig. 10.2 A quadrupole assembly . . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . . 186
Fig. 10.3 Passage of ion through a quadrupole assembly during ion
filtering. Only the selected ions pass through to the mass
analyzer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Fig. 10.4 High-performance liquid chromatography (HPLC) system with
its various components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Fig. 11.1 An abridged classification of statistical data . . . . . . . . . . . . . . . . . . . . . . 209
Fig. 11.2 Statistical decision tree for continuous parametric data with
normal distribution . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . 212
Fig. 11.3 Statistical decision tree for continuous parametric heterogeneous
data . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 213
Fig. 11.4 Statistical decision tree for nonparametric (not normal
distributed) data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Fig. 11.5 Statistical decision tree for categorical or quantal response
data . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 215
List of Figures xxix
Fig. 13.1 Equilibrium dialysis method for studying the extent of drug-
protein binding using dialysis tube. The upper figure shows
that both the ends of the tube are clipped. The lower picture
shows that both the ends of the tube are tied . . . . . . . . . . . . . . . . . . . . . 238
Fig. 13.2 Equilibrium dialysis chamber for studying the extent of drug-
protein binding. The figure shows that a dialysis membrane
separates the plasma compartment and the buffer compartment 239
Fig. 13.3 Laboratory scale ultrafiltration devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Fig. 13.4 An assembly for studying drug distribution and elimination in a
one-compartment open model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Fig. 13.5 A simple assembly for studying drug distribution and elimina-
tion in a one-compartment open model . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Fig. 13.6 An assembly for studying drug distribution and drug elimination
of the peripheral compartment in a two-compartment open model
system .. . . . . .. . . . . .. . . . . .. . . . . . .. . . . . .. . . . . .. . . . . .. . . . . . .. . . . . .. . . . . .. 254
Fig. 13.7 An assembly for studying drug distribution and elimination in a
three-compartment open model system. The drug is eliminated
from a peripheral compartment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Fig. 13.8 In vitro drug absorption using everted ileum. A portion of rat or
fowl ileum is used. It is everted (keeping inside out) and clipped
or tied at both the ends eventually after being filled with
deionized water. Then it is dipped into a drug solution (reservoir)
from where the drug is absorbed through the everted ileum into
the water inside . .. . .. . .. .. . .. . .. . .. . .. . .. . .. .. . .. . .. . .. . .. . .. . .. .. . .. 259
Fig. 13.9 Cellular internalization of FITC-labeled drug product (green
color) by c6 glioma cells cultured in DMEM (Dulbecco’s
Modified Eagle Medium)—supplemented with 10% fetal calf
serum and treated with 50 nM drug product. The cells were
nuclear-stained with DAPI (blue color). The photograph of the
cells incubated up to 4 h was taken with a confocal microscope 262
Fig. 13.10 A diffusion cell assembly for studying in vitro skin permeation of
drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
List of Tables
Table 4.1 Pharmacokinetic-related some selected Laplace transforms . . . . . . 71

Table 4.2 Logarithm table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Table 4.3 Antilogarithm table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Table 7.1 Drug–drug interactions and their systemic effects . . . . . . . . . . . . . . . 147
Table 9.1 Physiological zones of blood collection from small animals . . . 178
Table 9.2 Storage temperature of biological specimens . . . . . . . . . . . . . . . . . . . . 181
Table 13.1 Proforma for collection of retrospective patient data: Patients
suffered from chronic kidney disorder, received dialysis and
treatment in a hospital .. . . . . .. . . . . .. . . . .. . . . . .. . . . .. . . . . .. . . . .. . . . . . 280
Table 13.2 Proforma for collection of retrospective patient data: Drug-drug
interaction in intensive care unit (ICU) patients in a hospital . . 281
xxxi
Fundamentals of Pharmacokinetics
1
1.1 Fundamentals of Pharmacokinetics
The word “drug” was originated from the Greek word “pharmacon” or
“pharmakon,” and the meaning of the word “kinetics” is “in motion” or “positional
change concerning time.” Hence, the term “pharmacokinetics” implies that the drug
is in motion in vivo. When the drug is administered to a patient, several phenomena
occur in the body. When a patient takes a tablet as an oral dosage form of medicine,
upon reaching the stomach, sometimes the intestine (e.g., an enteric-coated tablet
intended to disintegrate in the intestine only), it disintegrates, and drug dissolution
takes place in the stomach/intestinal fluid. Eventually, drug molecules are absorbed,
and they reach the systemic circulation (in the blood). The drug molecules then
provide therapeutically effective drug level (i.e., the concentration of drug in the
blood on or above which drug can provide systemic therapeutic action/inhibitory
action for antibiotics), which is also called minimum effective concentration
(MEC) or minimum inhibitory concentration (MIC) of a drug in the blood
(Fig. 1.1). Drug transportation simultaneously begins to deliver drugs with an
effective concentration to the site of drug action. It produces its pharmacological
effect(s) (also called “pharmacodynamic action,” that is, how the body disposes of
an administered drug). While doing all such activities, the drug is also metabolized
and eliminated as metabolite or drug as such or both from the body. The absorption,
distribution, metabolism, and elimination (ADME) are the fundamental func-
tional and usually common phenomena of the drug while in motion in a living
system. All these processes involve the positional change of drugs in our bodies to
time. Hence, a vivid description of these phenomena (ADME) of a drug in vivo with
mathematical equations is called pharmacokinetics.
However, memorizing the equations and using them for the calculation cannot
help us understand the subject. Instead, only a proper and appropriate conceptualiza-
tion can build up the foundation of knowledge to understand pharmacokinetics.
ADME phenomena always vary for different drugs. ADME mainly depends on
# The Author(s), under exclusive license to Springer Nature Singapore Pte 1

Ltd. 2022
B. Mukherjee, Pharmacokinetics: Basics to Applications,
https://doi.org/10.1007/978-981-16-8950-5_1
2 1 Fundamentals of Pharmacokinetics
Fig. 1.1 The figure shows plasma drug concentration versus time curve that demonstrates how a
drug behaves in the blood after its absorption upon a single-dose administration by any routes other
than an intravenous route for systemic drug action. Various pharmacokinetic parameters of the drug
in the blood are also seen. The Cmax is the maximum plasma drug concentration at Tmax (time
taken to reach Cmax). The MEC is the minimum effective drug concentration to begin therapeutic
drug action. The MTC is the minimum toxic drug concentration, and it is also known as the
maximum safe drug concentration or the MSC. The plasma drug concentration between the MEC
and the MTC is called the therapeutic window. After a drug administration by oral route or by any
routes other than intravenous route, the time point at which the drug reaches minimum therapeuti-
cally effective drug concentration implies the onset of drug action
physicochemical characteristics of drugs such as drug dissolution, partition coeffi-

cient, surface activity, ionization of drug, isosterism, complexation, and biopharma-
ceutical characteristics such as drug–protein binding in the blood, drug transport,
drug absorption across the gastrointestinal membrane, rate and extent of drug
absorption, and degree of metabolism. Drugs directly administered into the blood
(by intravenous [i.v.] route, e.g., i.v. injection, i.v. bolus injection [a single volume
injection with a hefty dose of a drug for fast circulation in the blood], i.v. infusion)
do not have any absorption phenomenon.
Now we should understand why we require pharmacokinetic study. Several
scientific data have been provided accurately with mathematics, such as the height
of Mount Everest, the distance between the earth and the moon, and many physics
and chemistry theories. It is done due to the correctness of calculation with the help
of mathematics. It is because “mathematics depicts accuracy, provided the calcula-
tion is correct.” We determine the changes in drug concentration in the blood at
different time intervals in patients by analyzing the drug concentration of the blood
samples withdrawn from time to time. However, if we want to determine drug
concentrations in the brain, liver, heart, or lung at various time points after drug
administration in patients, the tissue samples to be taken from time to time from the
patients for drug analysis are not practically feasible. Although using the radio-
labeled drug, whole-body imaging at the different time points upon drug adminis-
tration can be done, but the method has several drawbacks and lacuna. None of the
1.1 Fundamentals of Pharmacokinetics 3
methods is generally acceptable as a practical approach for such studies. Thus,

without taking the tissue samples, by using pharmacokinetic equations and some
pharmacokinetic parameters, we can also accurately predict or determine drug
concentration in various tissues at different time points after administering a drug.
Thus, the study of pharmacokinetics is essential to understand behavioral patterns of
drugs in vivo without performing the actual experiments. Extremely logical and
validated mathematical equations, practically applicable mathematical models, and
appropriately selected set of conditions (assumptions) are the basis of
pharmacokinetics.
1.1.1 Pharmacokinetic Parameters and Blood Drug Profile
(Concept of Cmax, Tmax, bioavailability, area under the curve (AUC), following
intravenous bolus injection and infusion, therapeutic window, minimum effective
concentration, maximum safe drug level/toxic concentration, lag time, onset of
action, duration of action, first- and zero-order kinetics, biological half-life of drug)
The blood level of a drug means the plasma concentration of the drug. While a
conventional drug formulation for systemic drug effects is administered by any
routes (such as intramuscular [i.m.], intraperitoneal [i.p.], oral, buccal, pulmonary,
rectal, vaginal, nasal, etc.) other than the intravenous routes, drug upon administra-
tion is absorbed in the blood. Alteration of the drug amount in the blood varies with
time and the route of administration. However, the trend of drug absorption gener-
ally remains the same. Initially, the amount of drug increases and eventually reaches
the highest level (peak level), and then the drug level drops with the change in time
(Fig. 1.1). When a drug is administered directly into the blood by intravenous (i.v.)
injection or by intravenous infusion, the drug is distributed through the blood
circulation and then from the blood to various tissues and organs, including the
drug action site. Plasma concentration of drug alters differently from maximum to
minimum levels with time (Fig. 1.2) since the drug absorption phenomenon does not
occur here.
Once a drug is absorbed and reaches the MEC, the therapeutic action of the drug
is achieved. On and above the MEC, the drug provides its therapeutic action.
However, there is an upper level of the drug, on and above which the drug
concentration in the blood produces toxic action. It is called minimum toxic
concentration or maximum safe drug concentration (MTC/MSC) of the drug.
It is, therefore, essential to maintain the drug level between MEC and MTC to
provide optimum drug action without any toxic manifestations. The plasma drug
concentration between MEC and MTC of a drug is called its therapeutic window
(Fig. 1.1). There are two essential terms, lag phase and the onset of drug action, in
connection with a drug absorption phenomenon and blood level of the drug.
Interestingly, if we want to define them, it seems similar. It is, therefore, important
to understand the difference between the onset of drug action and the lag phase/lag
time. When a drug is administered by any route other than the intravenous route, the
length of time between the drug administration and achieving the MEC of the drug
Fig. 1.2 The figure shows plasma drug concentration versus time curve that shows how a drug
behaves after its single-dose administration by intravenous route. The MEC is the minimum
effective drug concentration to begin therapeutic drug action. The MTC is the minimum toxic
drug concentration, and it is also known as the maximum safe drug concentration or the MSC
(i.e., beginning of therapeutic action of the drug) is called the lag phase. On the other
hand, onset is the time point at which the drug reaches MEC after the administration
(interestingly, also measured as the length of time after drug administration at which
drug reaches MEC). That is why, it states that the time point after drug administration
to begin therapeutic drug action is called the onset of drug action. Therapeutically
effective drug concentration starts when a drug reaches its MEC and continues up to
when the drug from and above the MEC (after drug absorption) once again gets back
the MEC (Fig. 1.1). It is also called the bioavailability of the drug. The bioavailability
of a drug can be estimated in the most reliable way by determining the area under the
plasma drug concentration–time curve (AUC) from its bioavailable region. The
duration of drug action is the length of time when a drug provides therapeutic action
after its administration in a sequence of reaching the drug level at the MEC,
maintaining the drug level above the MEC, and then once again dropping it to the
MEC. Within a therapeutic window, the time point at which plasma drug concentra-
tion reaches the maximum level after the administration of a drug is called peak time
or Tmax, and the maximum plasma concentration of a drug is called Cmax. Further,
for a single dose, a fraction of the dose absorbed (F) in the blood (bioavailable) at
any time point is represented by multiplying dose by a ratio of drug absorbed in the
blood at any time point to the total amount of drug (in a dose) administered.
As stated earlier, drug administration directly into the blood by i.v. route does not
possess any drug absorption phenomenon to the blood. For a single i.v. injection of a
drug (Fig. 1.2), at the instantaneous moment of injection considering immediate
diffusion, Cmax reaches, and that instantaneous time point is Tmax for a single
i.v. injection of a drug. Again, the length of the period from the time of i.v. injection
of a drug to reaching its MEC is the duration of action of the drug. However, as no
absorption phenomenon is applicable here, the lag phase is equally not applicable for
i.v. drug injection. The drug can provide therapeutic action immediately in the blood
(e.g., antibiotics can start immediate action on bacteria present in the blood). But to
reach the tissues to provide drug action, drug distribution from the blood to the
tissues through the blood is necessary, and it needs additional time. The period also
varies depending on the various physicochemical and biopharmaceutical properties
of drugs.
Pharmacokinetic ADME phenomena can be well described using various kinetic
equations. The fundamental target of pharmacokinetics is to determine various rates,
such as rate of drug absorption, rate of drug–protein bindings, rate of drug distribu-
tion, rate of drug metabolism, and rate of elimination of drug or its metabolites, or
both, by using or developing rate equations. Besides, many mathematical equations
and models are used to determine other drug-related phenomena such as steady-state
plasma concentration, dose, drug plasma and drug tissue concentrations at various
time points after the drug administration and many more. Different mathematical
kinetic models follow drug behavior in our bodies. They include zero-order kinetics,
first-order kinetics, mixed-order kinetics, and many more. The drug absorption or
drug elimination sometimes undergoes essentially at a constant rate independent of
the drug concentration. It is well represented as zero-order kinetics. In terms of the
zero-order kinetic equation, if the amount of drug to be absorbed or eliminated is x at
time t, then the rate of change of drug is represented by dx dt ¼ k 0 , where k0 is the
proportionality constant (here the rate of drug absorption/elimination, is always
represented by the unit, mass/time). Minus () sign indicates that the amount of
drug decreases from its initial amount in either process (absorption/elimination) with
the increasing time.
Now, if we integrate the equation from an initial time point of drug administra-
tion, i.e., say, “0” time to any time “t,” when at t ¼ 0, and the amount of drug present,
say x0, and at a time “t,” the amount of drug in the blood, say, xt, then, we can write
Z t Z t
dx ¼ k0 dt
0 0
xt
or ½x ¼ k0 ½t t0
x0
or ½xt x0 ¼ k0 ½t 0
or xt x0 ¼ k0 t
or xt ¼ x0 k0 t
The half-life (t1/2) of a drug in zero-order kinetics is the amount of drug that
becomes half of its initial amount, i.e., at half-life, xt becomes x20 ,
x0
or ¼ x0 k0 t 1=2
2
x0
or k 0 t 1=2 ¼ x0
2
x0
or t 1=2 ¼ 2
k0
The unit of it is the unit of time, that is, hour or second.
However, one of the kinetic models plays a significant role as it covers nearly
95% of drug behaviors in terms of rate equation in our body. It is the first-order
kinetics. For most drugs, absorption, distribution, metabolism, and elimination
follow the first-order kinetics as the drug concentration remains insufficient to
saturate the kinetic mechanism of such phenomena (absorption, distribution, metab-
olism, and elimination) (Wagner 1970). It implies the amount-/concentration-depen-
dent rate of change of drug in the body.
According to the first-order kinetics, after the administration of drug directly into
the blood (by i.v. route), the rate of change of the amount of drug (dx
dt) at any time (t) is
directly proportional to the amount of drug (x) present in the blood at that time.
dx
Thus, /x
dt
or dx
dt ¼ k:x, where k is the proportionality constant (here the rate of drug elimina-
tion from the blood)
dx
or ¼ kdt
x
Now, if we integrate the equation from an initial time point of injection, i.e., say,
“0” time to any time “t,” when at t ¼ 0 (at the instantaneous moment of drug
administration), the amount of drug present, say x0, and at a time “t,” the amount of
drug in the blood, say, xt, then, we can write
Z t Z t
dx
dt ¼ k dt
0 x 0
xt
or ½ log e x ¼ k½t t0
x0
or ½ log e xt log e x0 ¼ k ½t 0
or ½ log e xt log e x0 ¼ kt ð1:1Þ

xt
or log e ¼ kt
x0
or xt ¼ x0 ekt
During the elimination process, if the rate constant (k) is considered as KE and the
amount of drug at time t is xt, the equation becomes
xt ¼ x0 eK E t
In the case of an initial amount of drug (dose), (x0), is injected into the blood (by i.
v. route) of a patient and after time “t,” the amount of drug in the blood is, say, xt,
then xt ¼ x0 eK E t where KE is the elimination rate constant and “e” is the base of the
natural logarithm.
Hence, xt ¼ x0 eK E t may be considered as a significantly important and predomi-
nantly used equation of pharmacokinetics. This version of the equation is often used
to describe different drug pharmacokinetic behaviors in our bodies.
If the amount of drug in the blood at time t is xB, then
xB ¼ x0 eK E t ð1:2Þ
From Eq. (1.1), we get
½ log e xt log e x0 ¼ kt
or kt ¼ log e x0 log e xt
x0
or kt ¼ log e
xt
At the half-life (t1/2), the amount of drug becomes half of its initial amount, i.e., xt
becomes x20 ,
x0
or kt 1=2 ¼ log e x0
2
or kt 1=2 ¼ log e 2
0:693
or t 1=2 ¼
k
The unit of half-life (t1/2) is the unit of time, that is, second (s), minute (min), or
hour (h).
1.1.2 Multiple-Dose Regimen
(Equations for determination of the minimum and maximum plasma drug

concentrations in a multiple-dose regimen)
In a multiple-dose regimen (when several doses of the same drug is given to a
patient where each dose is given with a definite time gap, e.g., prolonged treatment
of a patient with an antihypertensive drug/an antidiabetic drug, use of antibiotics,
Fig. 1.3 In a multiple-dose (repeated-dose) regimen for oral/any routes other than the intravenous
route of drug administration for systemic drug action, plasma drug concentration versus time curve
for the first dose and subsequent doses show peak and valley appearance between the minimum
effective drug concentration (MEC) and the minimum toxic drug concentration (MTC) levels in the
blood. The maximum plasma concentration (Cmax) and time to achieve Cmax (Tmax) are shown
after the first dose in the drug absorption curve. Every individual peak represents the Cmax after
each dose at the respective Tmax
Fig. 1.4 In a multiple-dose (repeated-dose) regimen of the intravenous route of drug administra-
tion, plasma drug concentration versus time curve for the first dose and subsequent doses shows
peak and valley appearance between the minimum effective drug concentration (MEC) and the
maximum safe drug concentration (MSC) levels in the blood
etc.), the plasma concentration versus time curve commonly shows peak and valley
appearance (Figs. 1.3 and 1.4).
In a multiple-dose regimen, when a drug for systemic action is administered by
any routes other than the i.v. route, while drug absorption takes place, the drug
concentration in the blood eventually goes to a maximum level and then comes down
to the MEC. The next administered dose should reach the MEC before the earlier
dose touches at the MEC for maintaining a continuous plasma drug level for better
therapeutic efficacy, and the same is true for subsequent doses and so on. These “up
and down” curves from the doses provide a “peak and valley” appearance (Fig. 1.3).
The length of time between administering the subsequent doses is called dose
interval and denoted by “τ” (tau).
When the drug is directly administered into the blood (i.v. route) in a multiple-
dose regimen, the drug plasma concentration versus time curve also shows a “peak
and valley” appearance (Fig. 1.4).
In a multiple-dose (repeated-dose) regimen, the plasma concentration of a drug
along with its maximum and minimum plasma levels against each dose can be
determined. Let us consider that x0 is the amount of drug administered by
i.v. route (i.v. dose) to a patient. We can then derive the equations for the plasma
concentration of a drug along with its maximum and minimum plasma levels after
each dose, as the maximum and minimum drug plasma levels vary in each case. The
following equations are also applicable for the oral route of drug administration
where rapid absorption is considered and x0 amount of drug available in plasma
instantaneously after its oral administration.
After the first dose, the maximum amount of drug (x1)max in the plasma is x0.
If τ is the dosing interval, after the first dose, the minimum amount of drug in
plasma is (x1)min and
ðx1 Þmin ¼ x0 eK E τ (where t = τ and τ is the time length at the end of which
therapeutically effective minimum drug concentration is available) where KE is the
elimination rate constant and “e” is the base of the natural logarithm.
For the second dose, the maximum amount of drug, (x2)max, in plasma, is
(x1)min + x0.

Therefore, ðx2 Þmax ¼ x0 þ x0 eK E τ ¼ x0 1 þ eK E τ
Again, ðx2 Þmin ¼ ðx2 Þmax eK E τ

¼ x0 1 þ eK E τ eK E τ ¼ x0 eK E τ þ e2K E τ
For the third dose, the maximum amount of drug, (x3)max, in plasma, is
(x2)min + x0.

ðx3 Þmax ¼ ðx2 Þmin þ x0 ¼ x0 eK E τ þ e2K E τ þ x0

¼ x0 1 þ eK E τ þ e2K E τ

ðx3 Þmin ¼ ðx3 Þmax :eK E τ ¼ x0 1 þ eK E τ þ e2K E τ eK E τ

¼ x0 eK E τ þ e2K E τ þ e3K E τ
likewise, after the administration of n number of doses.

For the nth dose, the maximum amount of drug, (xn)max, in plasma, is
(xn 1)min + x0.

ðxn Þmax ¼ x0 eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ þ x0

¼ x0 1 þ eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ
For the nth dose, the minimum amount of drug, (xn)min, in plasma is
ðxn Þmin ¼ ðxn Þmax eK E τ

¼ x0 1 þ eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ eK E τ
Letus now consider that 1 þ eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ

ðn1ÞK E τ
e ¼s
Then, (xn)max ¼ x0 s and ðxn Þmin ¼ x0 s:eK E τ
We know
s ¼ 1 þ eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ ð1:3Þ
By multiplying both sides of the above Eq. (1.3) by eK E τ , we get Eq. (1.4)
(below):

eK E τ s ¼ eK E τ þ e2K E τ þ e3K E τ þ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ þ enK E τ
ð1:4Þ
Now, subtracting Eq. (1.4) from Eq. (1.3), we get

s ¼ 1 þ eK E τ þ e2K E τ þ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ

eK E τ s ¼ eK E τ þ e2K E τ þ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ þ enK E τ
s s:eK E τ ¼ 1 enK E τ

s 1 eK E τ ¼ 1 enK E τ
1 enK E τ
s¼
1 eK E τ
As we know, (xn) max ¼ x0 s, and ðxn Þ min ¼ x0 s:eK E τ
Therefore,

1 enK E τ
ðxn Þmax ¼ x0
1 eK E τ

1 enK E τ
ðxn Þmin ¼ x0 :eK E τ
1 eK E τ
Therefore, at any time t, the amount of drug present in the blood may be
K E τ
determined
h nK τ i the equation for (xn)min, where τ of e
using present outside the part
1e E
x0 1eK E τ is replaced by t, as the source of this t is from the variable time factor,
nK τ
t. Further, 1e E
1eK E τ
portion is entirely a constant and obtained from the result of
summation “s;” thus, replacement of any τ to t there leads to an error. Thus, the
equation becomes

1 enK E τ
ð xn Þ t ¼ x0 :eK E t
1 eK E τ
(where (xn)t is the minimum amount of drug present in the plasma at any time t after
the nth dose)
Mostly as pharmacokinetic data, the plasma concentration of a drug is used
instead of the amount of drug present in the blood/plasma (Gibaldi et al. 1969). If
cp is the plasma concentration of drug and vd is the volume of distribution of the
drug, then we can determine the minimum plasma concentration of the drug,
maximum plasma concentration of the drug, and plasma concentration of the drug
at any time t after the administration of “n” number of doses, by using the following
equations:

x 1 enK E τ
cp max ¼ 0 : ,cp :vd ¼ x0
vd 1 e K E τ

x0 1 enK E τ
cp min ¼ :eK E τ
vd 1 eK E τ

x 1 enK E τ
cp n ¼ 0 :eK E t ð1:5Þ
vd 1 eK E τ

x0 1enK E τ K E τ
cp min vd 1eKE τ :e
Therefore, ¼ ¼ eKE τ ð1:6Þ
cp max x0 1enK E τ
vd K τ
1e E
1.1.3 Apparent Volume of Distribution or Volume of Distribution

(vd)
The volume of drug distribution is more popularly known as the apparent volume
of distribution of the drug in the body and is denoted by vd.
The volume of drug distribution is a measure of the extent of drug distribution in
the body. It is estimated by determining the resulting plasma concentration immedi-
ately when the drug is administered by rapid intravenous injection/quick bolus
intravenous injection (Gibaldi and McNamara 1978; Levy and Yacobi 1974).
The volume of drug distribution is represented by
amount of drug in the body

Vd ¼
plasma drug concentration
or
intravenous bolus dose

Vd ¼
immediately estimated plasma drug concentration
1.1.4 Steady-State Plasma Concentration of Drug
We have already seen above that the maximum and minimum plasma drug
concentrations increase in the subsequent doses upon administering each dose in a
multiple-dosage regimen. But if the doses are continued to administer at the correct
dose intervals, the maximum and minimum plasma drug concentrations approach to
constant levels at a particular time point. At this stage, the maximum plasma drug
concentration becomes constant (a definite value), and the minimum plasma drug
concentration also provides a constant value (another definite value) (Fig. 1.5). But
those constant maximum and minimum plasma drug concentration values generally
remain different for different drugs. At this stage, the average drug plasma level thus
maintains a fairly consistent plateau level of the drug (Chiou 1979). This plasma
drug concentration level is called steady-state plasma concentration/steady-state
level of drug. It can be achieved by intravenous drug administration or drug
administration by any route (e.g., oral route) (Figs. 1.5 and 1.6). Steady-state drug
level is achieved as the overall intake of a drug remains fairly in a dynamic
equilibrium with eliminating the drug. In a multiple-dosage regimen, generally, the
time required to reach steady-state drug plasma concentration is equal to 4–5
biological half-lives (t1/2) of a drug. Steady-state plasma concentration/steady-state
level is usually denoted by c or css. However, as stated earlier, it generally varies for
different drugs.
Thus, without any controversies, mathematically steady-state drug level must be
achievable with infinite numbers of dosing, that is, “n” ¼ “ 1 . ”
Therefore, at n ¼ 1, enK E τ approaches to zero (0); then,
Fig. 1.5 The plasma drug concentration versus time curve upon drug administration by oral route/
any route other than the intravenous route for systemic drug action shows that in each of the
subsequent doses, the maximum and minimum plasma drug concentration values increase during
drug absorption at the initial phase. After administering several doses, the maximum and minimum
plasma drug concentration values become constant. The average plasma drug concentration at the
zone is called steady-state plasma drug concentration (css). At the steady state, the maximum
constant plasma drug concentration value is called steady-state maximum plasma drug concentra-
tion (css)max. Likewise, the minimum constant plasma drug concentration value is called the steady-
state minimum plasma drug concentration (css)min. MEC indicates minimum effective drug concen-
tration, MTC denotes minimum toxic drug concentration
Fig. 1.6 The plasma drug concentration versus time curve upon drug administration by intrave-
nous route shows that the maximum and minimum drug plasma concentration values increase upon
drug administration at the initial phase in each of the subsequent doses. After administering many
doses, the maximum and minimum plasma drug concentration values become constant. The
average plasma drug concentration at the region is called steady-state plasma concentration (css).
At the steady state, the maximum constant plasma drug concentration value is called steady-state
maximum plasma drug concentration (css)max, and the minimum constant plasma drug concentra-
tion value is called the steady-state minimum plasma drug concentration (css)min. MEC indicates
minimum effective drug concentration, MTC denotes minimum toxic drug concentration

x0 1
ðcp Þ1 ¼ :eK E t ðPlease see the Eq:ð1:5Þ, where t is a variableÞ
vd 1 eK E τ
ð1:7Þ
Similarly, we can obtain the maximum and minimum amounts of the drug in the
blood and the maximum and minimum plasma concentrations of the drug at an
infinite number of dosing (“n” ¼ “ 1 ”), while the drug is repeatedly administered in
a regular dose interval at the steady state (Vaughan and Tucker 1976). Therefore, at
“ ”
n ¼ “ 1 , ” that is, at the steady state,

1
The maximum amount of a drug in the blood is ðx1 Þmax ¼ x0 K τ
1e E

1
The minimum amount of a drug in the blood is ðx1 Þmin ¼ x0 eK E τ
1 eK E τ

x 1
The maximum plasma concentration of a drug is ðc1 Þmax ¼ 0 K τ
vd 1 e E
The minimum plasma concentration of a drug is ðc1 Þmin

x 1
¼ 0 K τ :eK E τ ð1:8Þ
vd 1 e E
It is important to understand that (c1)max and (c1)min are the maximum and
minimum plasma concentration values of a drug at the steady-state level (Fig. 1.5),
and an average of these two concentration levels is the steady-state plasma
concentration/steady-state level of a drug represented by c or css. In a multiple-
dosage regimen, the average drug concentration in plasma at the steady state is very
crucial as it provides the maximum efficacy of a drug without any toxicity. At the
R in a τ dosing interval, c is represented by
steady state,
τ
ðcp Þ1 dt
c ¼ 0
τ ¼ ðAUC Þ, at steady state during a dosing interval
Dose interval (AUC [area under
the curve] here represents the drug-bioavailability during a dosing interval at the
steady state)
At any time t, (cp)1 is again given by xv0d 1e1K E τ :eK E t (where t is a variable;
please see Eq. (1.7)).
Z τ Z
x0 τ
1 K E t
cp dt ¼ K E τ :e dt
0 vd 1 e
1
0
Z τ
x0 1 K E t x0 1
¼ e dt , is entirely a constant value
vd 1 eK E τ 0 vd 1 eK E τ
Z τ K E t τ K E τ
x0 1 e x0 1 e eK E :0
or cp 1 dt ¼ ¼
0 vd 1 eK E τ K E 0 vd 1 eK E τ K E K E
K E τ
x0 1 e 1 x0 1 1 eK E τ
¼ K τ þ ¼ K τ
vd 1 e E KE KE vd 1 e E KE KE

x 1 1 eK E τ
¼ 0
vd 1 eK E τ KE
Z τ
x
or cp 1 dt ¼ 0
0 v d KE
R τ
cp 1 dt
Therefore, c ¼ 0
τ
x0
¼ ðsteady‐state drug plasma concentrationÞ ð1:9Þ
vd K E τ
Then, c or css = vdxK0E τ [Please see Eq. (1.9).]
In the case of intravenous infusion given at a fixed rate xτ0 ¼ k0 ðsayÞ
k0
Then, css ¼ ð1:10Þ
vd K E
k0
or vd ¼
css K E
1.1.5 Drug Accumulation Factor
In a multiple-dosage regimen, accumulation of a drug in the body is usually

expected. This excess drug accumulation in the body (Krüger-Thiemer 1968) often
results in side effects and many unwanted harmful effects in a patient. The drug
accumulation factor may be defined as a ratio of the steady-state plasma concen-
tration of a drug to the average drug plasma concentration after its first dose in a
multiple-dosage regimen. The drug accumulation factor can be calculated in advance
and is a beneficial information to understand whether the drug would harm a patient
due to its tissue accumulation upon its long-term use.
The extent of drug accumulation in a patient can be estimated in different ways
(Ronfeld and Benet 1977). One such deduction is described here. After the adminis-
tration of n number of dosages of a drug in a patient with a regular dosing interval τ,
the average plasma concentration of the drug is
R τ
cp n dt
cn ¼ 0
τ
Again, plasma
drugconcentration at any time t after the nth dosing is
x0 1enK E τ
cp n ¼ vd 1eK E τ eK E t [Please see Eq. (1.5).]
Integrating the equation from 0 to τ, we get
R τ
cp n dt
cn ¼ 0
τ
Z τ Z τ
x0 1 enK E τ K E t x0 1 enK E τ
¼ :e dt ¼ eK E t dt
0 τvd 1 eK E τ τvd 1 eK E τ 0

x 1 enK E τ
, 0 is entirely a constant value
τvd 1 eK E τ

x0 1 enK E τ eK E t τ
¼
τvd 1 eK E τ K E 0
K τ
x0 1 enK E τ e E eK E :0
¼ :
τvd 1 e E K τ K E K E
K τ
x 1 enK E τ e E 1 x0 1 enK E τ 1 eK E τ
¼ 0 þ ¼
τvd 1 e K E τ KE KE τvd 1 e K E τ KE KE

x 1 enK E τ 1 eK E τ
¼ 0
τvd 1 eK E τ KE
x0
¼ 1 enK E τ
τvd K E
x0
Therefore, cn ¼ 1 enK E τ
vd K E τ
Again, the steady-state average plasma drug concentration css or c ¼ vdxK0E τ [Please
see Eq. (1.9).].
Then, cn ¼ cð1 enK E τ Þ (by replacing the value of vdxK0E τ by c)
cn
or ¼ 1 enK E τ
c
When n is equal to 1, that is, after the first dose, cc1 ¼ ð1 eK E τ Þ.
Again, cc1 ¼ ð1e1K E τ Þ ¼ accumulation factor
Therefore, accumulation factor } R} ¼ ð1e1K E τ Þ; since R is a ratio, it has no unit.
Using this equation, merely using the drug elimination rate and the dosing
interval in a multiple-(repeated) dose regimen, the extent of drug accumulation in
a patient can be quantified. It is useful when a patient takes a particular medication

regularly for an extended period, as seen for antidiabetic drugs, antihypertensive
drugs, etc. Further, the factor may be used to calculate the loading dose of the drug in
a repeated dosing regimen.
1.1.6 Krüger-Thiemer’s “Pharmacokinetic Factor”
Ekkehard Krüger-Thiemer established an equation of proportional relationship

between the necessary effective drug concentration to the minimum inhibitory
drug concentration at the equilibrium, that is, at the steady-state drug level. The
proportionality constant is called Krüger-Thiemer’s “factor” or Krüger-
Thiemer’s “pharmacokinetic factor.” It is denoted by “σ” (Krüger-Thiemer
1960; Krüger-Thiemer and Bunger 1965–1966).
In a multiple-dose regimen, Krüger-Thiemer’s “pharmacokinetic factor” is a ratio
of the necessary effective drug concentration to the minimum inhibitory drug
concentration at the steady state:
x0
vd
σ¼
ðc1 Þ min
or σ ¼ x0
[Please see Eq. (1.8).]
x0
vd : 1
eK E τ
vd
ð
1eK E τ Þ
1 eK E τ
or σ ¼
eK E τ
The pharmacokinetic factor depends on the drug characters such as bactericidal,
bacteriostatic, and degenerative and their antagonists. However, there is no rational
method so far available to determine the factor. The value of the factor may be
obtained by clinical observation and experience related to such drugs only.
1.1.7 Krüger-Thiemer Dose Ratio
In a multiple-dose regimen, the Krüger-Thiemer dose ratio (Krüger-Thiemer 1960;

Krüger-Thiemer and Bunger 1965–1966) provides us with the concept of the loading
dose. Krüger-Thiemer dose ratio is the ratio of a loading dose (x) to the mainte-
nance dose (x0) of a drug. Thus, it is used to calculate the loading dose. Krüger-
x ¼ ð1eK E τ Þ ¼ R (drug accumulation factor). This equa-
Thiemer dose ratio is x 1
0
tion enables us to determine the minimum fluctuation of drug level in plasma while
the loading dose is administered in a multiple-dose regimen such as
i.v. administration of antibiotics in severe infections.
1.1.8 Concept of a Loading Dose
In the case of a severe infection or acute or severe health crisis, a high initial
non-toxic dose of a drug is administered to control the progress of the disease
quickly. It is then followed by the administration of maintenance dose (usual dose)
of the drug to control the disease further. A loading dose is the sufficiently high first
dose selected so that the minimum plasma concentration of which is equal to the
minimum steady-state plasma concentration of the drug in its multiple-dose
(repeated-dose) regimen. That is, (c1)min ¼ (c1)min
x0 K E τ
Again, ðc1 Þmin ¼ e ,ðc1 Þmin vd ¼ x0 eK E τ , as for the first dose
vd
and ðc1 Þmin ¼ xv0d ð1e1K E τ Þ eK E τ ; when the first dose is a loading dose, x0 is replaced
by x* in the equation ðc1 Þmin ¼ xv0d eK E τ . Then, for a loading dose, ðc1 Þmin ¼ x vd e
K E τ
K E τ
As per the definition of a loading dose, x vd :e ¼ xv0d ð1e1K E τ Þ eK E τ
1
or x ¼ x0 ¼ x0 R ð1:11Þ
ð1 eK E τ Þ
x 1
or ¼ ¼ R ðdrug accumulation factorÞ
x0 ð1 eK E τ Þ
The loading dose and the maintenance dose are determined using the following
formula:
v c
Loading dose ¼ dF p, where F is the fraction of dose bioavailable, cp is the plasma
concentration of drug, and vd is the volume of distribution
Further, maintenance dose ¼ CL:cFss :τ (where CL is the clearance, css is the steady-
state plasma drug concentration, τ is the dosing interval, and F is the fraction of dose
bioavailable)
1.1.9 Relationship Between Elimination Rate Constant (KE)

and Steady-State Drug Plasma Concentration (css) from
Krüger-Thiemer Dose Ratio Concept
x 1
Since, ¼ ¼R
x0 ð1 eK E τ Þ
or x ¼ x0 R
x x0
or ¼ R
vd v d
Another random document with
no related content on Scribd:
of negroes in Puerto Rico, the number being only about 30,000,
for whom some $11,000,000 was paid the owners. That statement
gives a fair idea of the character of the population as
respects numbers and race." Several small adjacent islands are
regarded as belonging to Porto Rico and were included in the
cession to the United States. One of these, named Viequez,
about 15 miles long and 3 or 4 miles wide, is very fertile,
and has about 7,000 inhabitants. On another, called Culebra,
there are some 600 or 700 people. The remaining islands are
smaller and unimportant.
56th Congress, 1st Session,

Senate Document Number 147, pages 1-2.
PORTO RICO:
The government as it was under Spanish rule.
"The civil government of the island was the Governor-General,

and the Governor-General was the civil government. All power
was lodged in his hands and he was accountable only to Madrid.
He was at once the executive, the legislative, and the judicial
head. As Captain-General, he had chief command of the military
forces, and made such disposition of them as he chose; as
Governor-General, he conducted civil affairs, whether insular
or municipal, according to his own pleasure. … If, as
occasionally happened, he was a wise and good man, seeking the
welfare of the people rather than his own personal enrichment
or the advancement of his political friends, there was less
cause for complaint from the people, who were completely
ignored. As the position was one of great power and of large
opportunities for pecuniary profit, it not infrequently went
to those who were prepared to exploit it in their own
interests. …
"The system of autonomy, which was proclaimed November 25,

1897 [see, in this volume, CUBA: A. D. 1897 (NOVEMBER)], was
never fully installed. The war intervened, and the provincial
legislature, which was its most important feature, was
dissolved when Sampson's fleet appeared, and the
Governor-General conducted the government practically on the
old plan, except that the ministry, as provided by the
autonomistic law, was retained, as follows: Secretary of
government or of state, secretary of the treasury, secretary
of the fomento or interior, including public works, public
instruction, public lands, mines, etc., agriculture and
commerce, and secretary of justice and worship. The last three
secretaries were subordinate to the secretary of government,
through whom all orders from the Governor-General and all
communications to or from him must pass. The autonomist law
allowed the secretaries or ministers to be members of one or
the other of the two legislative chambers. The
Governor-General with his council constituted the executive
power. No act of his was valid unless approved by one of the
secretaries, and the secretaries could issue no order which he
had not countersigned. He had the power to convoke or dissolve
the chambers, to refer objectionable bills to Madrid for
approval or disapproval, and to appoint or remove the
secretaries. All matters of a diplomatic character were in his
hands exclusively, and, constituted by the Pope patronato
real, he was the head of the church in the island and
practical director of ecclesiastical affairs. The legislature
consisted of two chambers, the council and the house of
representatives. The council was composed of fourteen members,
eight of whom were elected, and six appointed by the Crown;
the house of representatives of one representative for each
25,000 inhabitants, elected by the people. The liberality of
this law is further indicated by the fact that it gave the
right of suffrage to all males of 25 years of age and over.
The two chambers were empowered to legislate on all insular
questions, such as the estimates, which must be adopted by the
Cortes at Madrid, public instruction, public works,
sanitation, charities, etc. It will be seen that the reforms
granted by this autonomistic decree were large in the letter,
taking powers which the Governor-General had exercised
unquestioned and giving them to the people, who had never been
allowed to participate in the government of their own country.
Whether it would have proved liberal in practical operation is
not so certain. The Government invariably discriminated
against Porto Ricans in favor of Spaniards, and it is also to
be remembered that Spanish laws as written and Spanish laws as
administered are not always identical."
H. K. Carroll (Special Commissioner),

Report on Porto Rico, 1899, pages. 15-16.
PORTO RICO: A. D. 1898 (May).

American bombardment of forts at San Juan.
See (in this volume)

UNITED STATES OF AMERICA:
A. D. 1898 (APRIL-JUNE).
PORTO RICO: A. D. 1898 (July-August).

American conquest of.

A. D. 1898 (JULY-AUGUST: PORTO RICO).
PORTO RICO: A. D. 1898 (July-December).

Suspension of hostilities.
Cession to the United States.

A. D. 1898 (JULY-DECEMBER).
PORTO RICO: A. D. 1898-1899 (August-July).

Popular feeling in the Island on the American occupation.
Welcome to the Stars and Stripes.
Expectations and desires of the people.
Their character.
Extent of illiteracy.
The Peones.
"All classes of natives of the island welcomed the American

Army, American occupation, and American methods, and accepted
without hesitation the Stars and Stripes in place of the red
and yellow bars. They had not been disloyal to the old flag;
but it had come to represent to them, particularly during the
present century, in which a class feeling developed between
the insular and the peninsular Spaniard, partiality and
oppression. In the short war, some of the natives occupying
official positions made demonstrations of loyalty to the Crown
of Spain, as was perfectly natural, but they were among the
first to submit to American rule when the protocol promised
cession of the island to the United States. On the other hand,
as the commissioner is informed, a Porto Rican who had hoped
and prayed for American intervention for fifty years enrolled
himself as a Spanish citizen some months after the war was
concluded, and his hopes had been realized. Porto Ricans
generally complained that the former Government discriminated
in favor of the Spaniard, who, in the distribution of the
offices, was preferred to the native, and who, aided by the
powerful influence of the authorities, prospered in business
as banker, merchant, manufacturer, or agriculturist. They also
insist that the internal improvement of the island was
neglected; that agriculture bore more than its share of the
burden of taxation; that the assessments were very inequitable
and unequal; that education was not fostered, and that in
general the welfare of the people was not the first concern of
their rulers.
{411}
"They expect under American sovereignty that the wrongs of

centuries will be righted; that they will have an honest and
efficient government; the largest measure of liberty as
citizens of the great Republic under the Constitution; home
rule as provided by the Territorial system; free access to the
markets of the United States and no customs duties on goods
coming from our ports; a school system modeled after that of
the United States; the adoption of the English language in due
time and the general adaptation to the island of all those
institutions which have contributed to the prosperity,
progress, and happiness of the American people. The largest
and most representative gathering, since American occupation,
was held in San Juan, October 30, 1898, without distinction of
party or class with the object of consultation and formulation of
a programme for the future. In brief, the propositions of the
congress as submitted to the commissioner for presentation to
the President of the United States were these: Immediate
termination of military and inauguration of civil government;
establishment of the Territorial system, with laws common to
other Territories of the Union; a legislature in two branches;
suffrage for all male citizens of 21 years of age or over, the
right to be surrendered at the end of the first two years by
those who do not then know how to read and write; judicial
reform; introduction of the jury system; autonomy for
municipal governments; taxation on the basis of valuation;
free and reciprocal commerce with the ports of the United
States; aid for agriculture; obligatory and universal
education; trade schools; savings banks. This programme of
reforms seems to have very general support, although there is
a difference of opinion on certain points. Many Porto Ricans
urged the commissioner to represent them as desiring that the
military regime be made as short as possible, not because the
military governors were in any way objectionable or their rule
oppressive, but because the civil status of the island should
be fixed with no unnecessary delay. There was no other opinion
except among foreign subjects, many of whom thought that the
people were not yet ready for self-government, and that the
firm hand of military power would be needed for probably two
years. …
"If the desire to assume the burdens of local self-government
may be taken as indicating some degree of capacity for
self-government, the people of Porto Rico certainly have the
desire. They may be poor, but they are proud and sensitive,
and would be bitterly disappointed if they found that they had
been delivered from an oppressive yoke to be put under a
tutelage which proclaimed their inferiority. Apart from such
qualifications as general education and experience constitute,
the commissioner has no hesitation in affirming that the
people have good claims to be considered capable of
self-government. Education and experience, although too high
a value can hardly be set upon them, do not necessarily make
good citizens. … The unswerving loyalty of Porto Rico to the
Crown of Spain, as demonstrated by the truth of history, is no
small claim to the confidence and trust of the United States.
The people were obedient under circumstances which provoked
revolt after revolt in other Spanish colonies. The habit of
obedience is strong among them. Their respect for law is
another notable characteristic. They are not turbulent or
violent. Riots are almost unknown in the island; so is
organized resistance to law; brigandage flourished only for a
brief period after the war and its object was revenge rather
than rapine. They are not a criminal people. The more violent
crimes are by no means common. Burglary is almost unknown.
There are many cases of homicide, but the number in proportion
to population is not as large as in the United States.
Thievery is the most common crime, and petty cases make up a
large part of this list of offenses. The people as a whole are
a moral, law-abiding class, mild in disposition, easy to
govern, and possess the possibilities of developing a high
type of citizenship."
H. K. Carroll (Special Commissioner),

Report on Porto Rico, 1899, pages 55-57.
"On the 25th day of July, 1899, an election was held in

Adjuntas for municipal officers, and the registration was made
in conformity to General Orders, No. 112, c. s., Headquarters
Department of Puerto Rico. The order imposed the following
qualifications for electors: Men over 21 years old, able to
read and write, or who were taxpayers of record, who had been
actual residents of the island for at least two years, and of
the municipality for six months preceding the date of the
election. The number who proved these qualifications before
the board of registration was 906, out of a population,
according to the census of 1897, of 18,505; that is, less than
5 per cent could vote under the conditions stated. There was
much public interest in this election, and it is believed that
about all who were eligible were registered. This incident
indicated that in the whole island there may be approximately
45,000 who could vote under the conditions of the order above
referred to. The class who can not fulfill these conditions,
say 75 per cent of the males over 21 years of age, are usually
in a state of abject poverty and ignorance, and are assumed to
include one-fifth of the inhabitants. They are of the class
usually called peones. This word in Spanish America, under old
laws, defined a person who owed service to his creditor until
the debt was paid. While those laws are obsolete, the
condition of these poor people remains much as before. So
great is their poverty that they are always in debt to the
proprietors or merchants. They live in huts made of sticks and
poles covered with thatches of palm leaves. A family of a
dozen may be huddled together in one room, often with only a
dirt floor. They have little food worthy of the name and only
the most scanty clothing, while children of less than 7 or 8
years of age are often entirely naked. A few may own a machete
or a hoe, but more have no worldly possessions whatever. Their
food is fruit, and if they are wage-earners, a little rice and
codfish in addition. They are without ambition and see no
incentive to labor beyond the least that will provide the
barest sustenance. All over the island they can be seen to-day
sitting beside their ruined huts, thinking naught of
to-morrow, making no effort to repair and restore their cabins
nor to replant for future food.
{412}
"The remarks of Mr. James Anthony Froude in his work on 'The

English in the West Indies' apply with full force to these
people: 'Morals in the technical sense they have none, but
they can not be said to sin because they have no knowledge of
law, and therefore they can commit no breach of the law. They
are naked and not ashamed. They are married but not parsoned.
The women prefer the looser tie, that they may be able to lose
the man if he treats her unkindly. Yet they are not
licentious. … The system is strange, but it answers. … There
is evil, but there is not the demoralizing effect of evil.
They sin, but they sin only as animals, without shame, because
there is no sense of doing wrong. They eat the forbidden
fruit, but it brings with it no knowledge of the difference
between good and evil. … They are innocently happy in the
unconsciousness of the obligations of morality. They eat,
drink, sleep, and smoke, and do the least in the way of work
they can. They have no ideas of duty, and therefore are not
made uneasy by neglecting it.' Between the negro and the peon
there is no visible difference. It is hard to believe that the
pale, sallow, and often emaciated beings are the descendants
of the conquistadores who carried the flag of Spain to nearly
all of South America, and to one-third of North America."
General George W. Davis,

Report on the Civil Government of Puerto Rico,
September 30, 1899
(Message and Documents: Abridgment, 1899-1900,
volume 2, pages 1293-1294).
"The educated class of Puerto Ricans are as well educated and

accomplished as the educated men of any country. They have had
the benefit of a liberal education, a few in the United
States, a good many in France, and a great many in Madrid and
Habana, where they have passed through the universities. The
lawyers and doctors are all graduates of either the university
in Habana or some university in Spain, with very few exceptions.
The merchants are largely Spanish, many of whom will probably
preserve their nationality under the provision of the Treaty
of Paris which gives them that right. A few may adopt American
citizenship, and ultimately possibly all will, but many of the
merchants who conduct the largest part of the business of
Puerto Rico will retain their Spanish citizenship. There are a
number of merchants who are natives, a few Germans, and a few
English. I do not remember any American merchant in business
there before the occupation. The schools in Puerto Rico
conducted under the Spanish system were few in number. The
amount allotted for education by the insular budget was
something like 300,000 pesos a year, as I now recall the
figures. The teachers were officers of the government, holding
life positions and receiving pensions when superannuated. They
belong to a civil-service class which is not dependent upon
any change of administration, only being removed for cause.
The lawyers, or judges, rather, of the island, occupy a
similar position."

Testimony before Senate Committee.
(56th Congress, 1st Session, Senate Document. No. 147).
PORTO RICO: A. D. 1898-1899 (October-October).

The military government instituted by the United States.
"The government of the island, its various civil institutions,

its codes and its courts, the systems of taxation, etc., have
been modified in very important particulars since the American
occupation began, October 18, 1898. It will be useful, perhaps,
to indicate the more important changes. Under General John R.
Brooke [in command of the Department, October 18 to December
5, 1898] orders were issued declaring
(1) That the political relations of Porto Rico with Spain were
at an end; that provincial and municipal laws were in force in
so far as not incompatible with the changed conditions, and
that they would be enforced substantially as they were before.
(2) Abolishing the use of all stamped paper and stamps of

every kind for documents, public and private.
(3) Exempting all conveyances and contracts from the payment

of royal dues.
(4) Discontinuing the diputacion provincial, and distributing

its duties among the secretaries or ministers.
(5) Directing that appeals should not be sent to the supreme

court in Madrid, but should be heard by the superior court at
San Juan.
(6) Abolishing the subdelegation of pharmacy which gave

degrees to pharmacists.
(7) Making the fisheries free to all.
Appropriations for the support of the church ceased with

American occupation, and the Government lottery was
discontinued.
"Under the military government of General Guy V. Henry

[December 6, 1898 to May 8, 1899], orders were issued:
(l) Appointing military commissions to try cases of arson and

murder which had accumulated in the civil courts.
(2) Closing public offices on Sunday, as far as possible.
(3) Suspending the municipal tax on fresh beef for use of the
Army.
(4) Making Christmas and New Year's holidays.
(5) Forbidding grants or concessions of public or corporate

rights or franchises without the approval of the commanding
general and the Secretary of War.
(6) Abolishing the municipal consumo tax on articles of food,

fuel, and drink, and providing for additional assessments on
the sale of liquors and tobacco.
(7) Separating the collection of customs duties from that of

direct taxes.
(8) Establishing a new system of land taxation, by which

agricultural lands should be taxed according to the several
classes instituted, from 1 peso down to 25 centavos per
cuerda, and levying 50 per cent additional on lands whose
owners reside abroad.
(9) Providing for the free vaccination of the people of the

island.
(10) Prohibiting the exhumation of bodies in the cemeteries,

recognizing the right of priests to control burials in
consecrated grounds, and requiring municipalities to keep
cemeteries in repair.
(11) Reducing notarial fees from $1.88 to $1, from $4.50 to

$1, from $11 to $1, and from $1 to 50 cents, according to
class of document, and canceling others.
(12) Reorganizing the cabinet, so as to make all the

secretaries directly responsible to the governor-general.
(13) Suspending the foreclosure of mortgages on agricultural

property and machinery for one year.
(14) Appointing February 22 a holiday.
(15) Prohibiting the sale of liquor to children under 14 years

of age.
(16) Modifying the civil marriage law.
(17) Declaring that eight hours shall constitute a day's work.
(18) Creating an insular police.
{413}
"Under the military government of General George W. Davis

[May 8, 1899, to May 1, 1900], orders were issued
(1) Modifying the order of
General Henry concerning hours of labor, so as to allow

agreements between employer and employee for longer or shorter
hours.
(2) Naming May 30 as a holiday.
(3) Allowing the writ of habeas corpus to be issued.
(4) Constituting a board of prison control and pardon.
(5) Continuing the observance as a holiday of June 24.
(6) Creating a provisional court on the basis of circuit and

district courts of the United States for the hearing of cases
not falling within the jurisdiction of local insular courts.
(7) Creating a superior board of health for the island.

(8) Reorganizing the bureau of public instruction and the
system of education.
(9) Relieving the judiciary from all control by the department

of justice, discontinuing the office of secretary of justice,
and appointing a solicitor-general.
(10) Abolishing the sale at auction of the privilege of

slaughter of cattle, and making it free.
(11) Reorganizing the judicial system of the island, with a

supreme court in San Juan and district courts in San Juan,
Ponce, Mayaguez, Arecibo, and Humacao, and with modifications
of civil and criminal procedure.
(12) Discontinuing the departments of state, treasury, and

interior, and creating bureaus of state and municipal affairs,
of internal revenue, and of agriculture, to be placed under
the direction of a civil secretary, responsible to the
governor-general, and continuing the bureaus of education and
public works, with an insular board of nine members to advise
the governor-general on matters of public interest referred to
them.
"The reductions in the budget of expenditures have been

extensive. That of 1898-99, adopted in June, 1898, amounted to
$4,781,920, native money. The appropriations for 'general
obligations,' which went to Madrid, $498,502, for the clergy,
$197,945; for the army, $1,252,378; for the navy, $222,668,
making a total of $2,171,493, ceased to be obligations,
leaving $2,610,428 for the fiscal year. A new budget was
adopted for the calendar year 1899, which still further
reduces expenditures, calling only for $1,462,276. This
budget, if carried out, would have involved a reduction from
the proposed budget of 1898-99 of $3,319,644; but a new budget
was formed, as already stated, for 1899-1900, which appears to
call for an increase over this very moderate sum. The revenues
were reduced by the abolition of stamped paper, personal
passports, export duties, royal dues on conveyances, the
lottery system, and other sources of income, amounting, all
told, to less probably than a million of pesos."
H. R. Carroll (Special Commissioner),

Report on Porto Rico, October 6, 1899, pages 53-55.
PORTO RICO: A. D. 1899 (August).

Destructive cyclone.
"On the morning of the 7th of August, 1899, the United States
Weather Bureau, through its branch establishment here,
announced the approach of a cyclonic disturbance, and the
danger signal was ordered to be hoisted at substations of the
Bureau at Ponce and Mayaguez. At the same time I directed that
the danger be reported to all commanding officers of posts
throughout the island. There had been no serious or
destructive storm in Puerto Rico since 1867, and the
inhabitants had ceased to feel great concern on account of
tropical tempests. Except at seaports, little heed was given
to the caution, and in some cases the telegraph operators
failed to receive or to promptly deliver the warning messages.
The vortex of the cyclone appears to have traversed the island
throughout its whole length, from about Humacao to Mayaguez,
and its path was a scene of very great devastation. … The gale
struck the island at Humacao about midnight of August 7, and
furiously blew all the rest of that night and well into the
next day, while at Mayaguez the violence was not great until 9
o'clock on the morning of the 8th. But as the latter town was
under the lee of high mountains, it suffered much less than it
would have done had it been higher or not thus protected. Most
of the habitations in the track of the center of the cyclone
were entirely smashed and the débris strewn all over the
country. The full reports of the loss of life bring the number
of deaths up to 2,700. The wind worked dreadful havoc with nearly
everything useful to man. Besides the mortality, which was
appalling, the material damage was almost beyond belief. But
the greatest loss of life resulted, not from the wind, but
from the terrible downfall of rain that immediately followed.
… Added to the horror of the situation there came with the
gale on the southern coast a tidal wave, which submerged large
areas with sea water and swept away what the wind and rain had
spared, in some places completing the destruction. Every river
bed or bottom of a land depression was a roaring torrent. The
wind uprooted myriads of trees, and the rain, entering and
permeating the soil, loosened it, and on steep declivities
resulted in avalanches of earth, mud, and water, covering wide
areas and piling up the debris in the ravines and gorges. … The
material loss to the coffee growers can as yet only be
estimated, but the most conservative figures received place
this year's crop at one-third of the normal. … Regard being
had to the fact that five years must elapse before the coffee
trees and their shade can be replanted and reach a normal
bearing condition, the total loss can not be safely placed
below 25,000,000 pesos for Puerto Rico on account of this
hurricane."

Report (Message and Documents: Abridgment, 1899-1900,
volume 2, pages 1343-1344).
PORTO RICO: A. D. 1899 (October).

Census of the Island taken under the direction of the
War Department of the United States.
"The population of Porto Rico shown by the schedules of the

present census taken with reference to the date of October 16,
1899, was 953,243. This was about nine-tenths of the
population of Maryland in 1890, the State whose population is
nearest to that of Porto Rico. … If the figures for … earlier
censuses may be accepted, it appears that the population of
Porto Rico has been growing through the last twelve years with
greater rapidity than before since 1860. Its present rate of
increase is about the same as that of Ohio, Tennessee, or the
Carolinas during the decade between 1880 and 1890. … It
appears that the average increase of population in the
interior has been more rapid than that on the coast. If the
figures for the coast cities of San Juan, Ponce, and Mayaguez
had been excluded, the difference would be yet more marked.
The depressed condition of sugar-cane growing in the West
Indies of recent years may have played an important part in
producing this difference, for the growing of sugar cane is
prevalent in the coast plains of Porto Rico.
{414}
"The area of Porto Rico, including the adjacent and dependent

islands of Vieques, Culebra, Mona, and Muertos, has been
measured in connection with this census and found to be 3,606
square miles. But owing to the imperfect surveys on which all
maps of Porto Rico are based there must be a considerable and
indeterminate margin of possible error in any such
measurement. The island is about three times the size of Long
Island, which was in 1890 perhaps the largest insular division
of the United States. It is also slightly greater than the
eastern shore of Maryland (3,461 square miles). … Porto Rico
has 264 persons to a square mile. This density of population
is about the same as in Massachusetts, twice that in New York
State, and thrice that in Ohio. It is more than seven times
that of Cuba and not much less than twice that of Habana
province. …
"The people of Porto Rico are, in the main, a rural community.

There are no large cities in the island, the two largest being
San Juan, which, regarding the entire municipal district as a
city, had a population of 32,048, and Ponce, which with its
port constituted practically one city, with a population of
27,952. These are the only two cities exceeding 25,000
inhabitants. The next city of magnitude is Mayaguez, on the
west coast, with a population of 15,187. The only other city
exceeding 8,000 inhabitants is Arecibo, with a population of
8,008. The total urban population of the island contained in
cities exceeding 8,000 inhabitants each is 83,195, or only 8.7
per cent of the population of the island. This is a much
smaller proportion than in Cuba, where the corresponding
figures are 32.3 per cent, or in the United States, where the
corresponding proportion in 1890 was 29.2 per cent. There are
in Porto Rico 57 cities, each having a population of 1,000 or
more. The total urban population of the island, under this
definition, numbers 203,792, or 21.4 per cent of the total
number of inhabitants of the island. Similar figures for Cuba
show 47.1 per cent of the population of that island."
Census of Porto Rico, Bulletin No.1.
PORTO RICO: A. D. 1899-1900.

The question of the tariff treatment of its new Territory
by the United States Government.
Writing in "The Forum," November, 1899, Mr. H. K. Carroll, who

had investigated the conditions in Porto Rico as a Special
Commissioner of the United States government, described the
obligation which, in his view, they imposed on the latter as
follows: "The only free market the Puertorican has for his
products is the island market. All the rest of the world is
closed to him. He cannot even buy in a free market; everything
he buys as well as everything he sells being subject to
duties. This is the penalty of independence; but Puerto Rico
is not, and does not want to be, independent. She wants such
commercial relations with us as Alaska, New Mexico, and
Arizona have, and desires a territorial form of government. I
am of the opinion that we cannot refuse these reasonable
requests without doing great injustice to Puerto Rico. It must
be remembered that we sought Puerto Rico; for Puerto Rico did
not seek us. We wrested her from the sovereignty of Spain,
without asking her if she desired to change her allegiance. We
were of the opinion that she was not justly treated by Spain;
that she was governed in the interests of the mother country
solely; that she was oppressed and overtaxed and denied a
proper measure of home rule; and that in consequence we were
serving the cause of humanity in breaking the chains that
bound her. This was what the Puertoricans thought also. They
welcomed our troops and our control. They were glad to turn
their backs on the history of the past, and begin under the
glorious Republic of the North a new and more prosperous
career. They are disappointed, perhaps unreasonably, that
their new life has not already begun; they are eagerly
expectant. They look to the President to recommend, and to
Congress to adopt, a system of government which will make the
island a Territory, equal in rank and rights and privileges to
existing Territories. They ought not to be disappointed
without the best and strongest of reasons. Three reasons are
mentioned in opposition to the granting of territorial
government to Puerto Rico. First, admission as a Territory
implies ultimate admission to statehood; and statehood for
islands separated as Hawaii and Puerto Rico are by from 1,200
to 2,500 miles from the United States is not to be thought of
for a moment. Second, territorial organization involves the
relinquishment of customs duties; and the cane and tobacco
growers of our West India possession would have free access to
the markets of the United States, and thus come into injurious
competition with our own farmers. Third, the people of Puerto
Rico are not competent for the measure of self-government
which the territorial system provides."
This most reasonable and just view of the duty of the American
people to their new fellow citizens received strong
endorsement from higher official authority in the subsequent
annual report of the Secretary of War, who said: "It is plain
that it is essential to the prosperity of the island that she
should receive substantially the same treatment at our hands
as she received from Spain while a Spanish colony, and that
the markets of the United States should be opened to her as
were the markets of Spain and Cuba before the transfer of
allegiance. Congress has the legal right to regulate the
customs duties between the United States and Porto Rico as it
pleases; but the highest considerations of justice and good
faith demand that we should not disappoint the confident
expectation of sharing in our prosperity with which the people
of Porto Rico so gladly transferred their allegiance to the
United States, and that we should treat the interests of this
people as our own; and I wish most strongly to urge that the
customs duties between Porto Rico and the United States be
removed."
Message and Documents:

Abridgment, 1899-1900, volume 2, page 757.
And, finally, the President of the United States, in his

Message to Congress, December 5, 1899, gave his high authority
to the declaration that this duty of his government to Porto
Rico was "plain": "It must be borne in mind," he said, "that
since the cession Porto Rico has been denied the principal
markets she had long enjoyed and our tariffs have been
continued against her products as when she was under Spanish
sovereignty. The markets of Spain are closed to her products
except upon terms to which the commerce of all nations is
subjected. The island of Cuba, which used to buy her cattle
and tobacco without customs duties, now imposes the same
duties upon these products as from any other country entering
her ports.
{415}
She has therefore lost her free intercourse with Spain and
Cuba, without any compensating benefits in this market. Her
coffee was little known and not in use by our people, and
therefore there was no demand here for this, one of her chief
products. The markets of the United States should be opened up
to her products. Our plain duty is to abolish all customs
tariffs between the United States and Porto Rico and give her
products free access to our markets."
Message and Documents: Abridgment,
volume 1, page 53.
Notwithstanding all which high official acknowledgments and

declarations of obligation and duty, on the part of the
Republic of the United States to the people of the island
which it had wrested from Spain, certain interests in the
former that objected to competition from the latter were able
to secure legislation which deferred the performance of the
"plain duty" required. An Act of Congress which the President
approved on the 12th of April, 1900, "temporarily to provide
revenues and a civil government for Porto Rico and for other
purposes," enacted as follows:
"SECTION 3.
That on and after the passage of this Act all merchandise
coming into the United States from Porto Rico and coming into
Porto Rico from the United States shall be entered at the
several ports of entry upon payment of fifteen per centum of
the duties which are required to be levied, collected, and
paid upon like articles of merchandise imported from foreign
countries; and in addition thereto upon articles of
merchandise of Porto Rican manufacture coming into the United
States and withdrawn for consumption or sale upon payment of a
tax equal to the internal-revenue tax imposed in the United
States upon the like articles of merchandise of domestic
manufacture; such tax to be paid by internal-revenue stamp or
stamps to be purchased and provided by the Commissioner of
Internal Revenue and to be procured from the collector of
internal revenue at or most convenient to the port of entry of
said merchandise in the United States, and to be affixed under
such regulations as the Commissioner of Internal Revenue, with
the approval of the Secretary of the Treasury, shall
prescribe; and on all articles of merchandise of United States
manufacture coming into Porto Rico in addition to the duty
above provided upon payment of a tax equal in rate and amount
to the internal-revenue tax imposed in Porto Rico upon the

Ebook Pharmacokinetics Basics To Applications Biswajit Mukherjee Online PDF All Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Ebook Pharmacokinetics Basics To Applications Biswajit Mukherjee Online PDF All Chapter

Uploaded by

Copyright:

Available Formats

Pharmacokinetics Basics to

Applications Biswajit Mukherjee

Rowland and Tozer s Clinical Pharmacokinetics and

High-Entropy Materials: From Basics to Applications 1st

Superconductivity Basics and Applications to Magnets

Lubricants and Waxes From Basics to Applications 1st

Semiconductors for Optoelectronics Basics and

Basic Pharmacokinetics, 3rd Edition Mohsen A. Hedaya

Handbook of Pharmacokinetics and Toxicokinetics Mehdi

Ascending Order Rohan Mukherjee

ISBN 978-981-16-8949-9 ISBN 978-981-16-8950-5 (eBook)

Pharmacokinetics: Basics to Applications is a textbook-cum-comprehensive guide-

Kolkata, India Biswajit Mukherjee

2.1.7 Method of Residual for Determination

5.1.4 Determination of Drug Metabolite Levels in Plasma

8.1.5 Physiological Effects on the Pharmacokinetic

12 Pharmacokinetic Software and Tools . . . . . . . . . . . . . . . . . . . . . . . 227

13.1.18 Determination of Metformin and Canagliﬂozin

Fig. 1.4 In a multiple-dose (repeated-dose) regimen of the intravenous

number of binding sites of a protein molecule for drug

protein molecule for drug molecules. “K” is the equilibrium rate

diffuses into the cells, and drug molecules/drug metabolites that

intravenous route in a patient. Data show that the drug avail-

compartments (here designated as compartment “2” and “3,”

Fig. 5.4 Plot of logarithmic plasma drug metabolite concentration

Table 4.1 Pharmacokinetic-related some selected Laplace transforms . . . . . . 71

1.1 Fundamentals of Pharmacokinetics

# The Author(s), under exclusive license to Springer Nature Singapore Pte 1

physicochemical characteristics of drugs such as drug dissolution, partition coefﬁ-

methods is generally acceptable as a practical approach for such studies. Thus,

1.1.1 Pharmacokinetic Parameters and Blood Drug Profile

or ½ log e xt log e x0 ¼ kt ð1:1Þ

From Eq. (1.1), we get

½ log e xt log e x0 ¼ kt

1.1.2 Multiple-Dose Regimen

(Equations for determination of the minimum and maximum plasma drug

Again, ðx2 Þmin ¼ ðx2 Þmax eK E τ

likewise, after the administration of n number of doses.

ðxn Þmin ¼ ðxn Þmax eK E τ

Letus now consider that 1 þ eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ

s ¼ 1 þ eK E τ þ e2K E τ . . . . . . : þ eðn2ÞK E τ þ eðn1ÞK E τ ð1:3Þ

Now, subtracting Eq. (1.4) from Eq. (1.3), we get

1.1.3 Apparent Volume of Distribution or Volume of Distribution

amount of drug in the body

intravenous bolus dose

1.1.4 Steady-State Plasma Concentration of Drug

The minimum plasma concentration of a drug is ðc1 Þmin

1.1.5 Drug Accumulation Factor

In a multiple-dosage regimen, accumulation of a drug in the body is usually

a patient can be quantiﬁed. It is useful when a patient takes a particular medication

1.1.6 Krüger-Thiemer’s “Pharmacokinetic Factor”

Ekkehard Krüger-Thiemer established an equation of proportional relationship

1.1.7 Krüger-Thiemer Dose Ratio

In a multiple-dose regimen, the Krüger-Thiemer dose ratio (Krüger-Thiemer 1960;

1.1.8 Concept of a Loading Dose

1.1.9 Relationship Between Elimination Rate Constant (KE)

56th Congress, 1st Session,

"The civil government of the island was the Governor-General,

"The system of autonomy, which was proclaimed November 25,

H. K. Carroll (Special Commissioner),

PORTO RICO: A. D. 1898 (May).

See (in this volume)

PORTO RICO: A. D. 1898 (July-August).