Introduction to Drug Disposition and Pharmacokinetics

Stephen H. Curry, Robin Whelpton

• Publisher: Wiley
• Year: 2016
• ISBN:
  9781119261056
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

The application of knowledge of drug disposition, and skills in pharmacokinetics, are crucial to the development of new drugs and to a better understanding of how to achieve maximum benefit from existing ones. The book takes the reader from basic concepts to a point where those who wish to will be able to perform pharmacokinetic calculations and be ready to read more advanced texts and research papers.

The book will be of benefit to students of medicine, pharmacy, pharmacology, biomedical sciences and veterinary science, including those who have elected to study the topic in more detail, such as via electives and special study modules. It will be of benefit to those involved in drug discovery and development, pharmaceutical and medicinal chemists, as well as budding toxicologists and forensic scientists who require the appropriate knowledge to interpret their findings and as an introductory text for clinical pharmacologists. Early chapters describe the basic principles of the topic while the later ones illustrate the application of those principles to modern approaches to drug development and clinical use. Full colour illustrations facilitate the learning experience and supporting material for course leaders and students can be found on the Companion Web Site

"Another book on PK? Yes and there should be and it should be DD & PK. It is good, unique, and does fill a currently unmet need for those working in the xenobiotic arena. DD & PK is just like the perfect mystery novel—the one "you just can't put down." However, unlike a mystery novel which requires only one reading to find the answer, the reader of DD & PK will learn more than an answer to a single question. The reader will find many solutions to a wide variety of mysterious problems associated with the time course and actions of xenobiotics."
— International Journal of Toxicology, John A. Budny, PhD, President, PharmaCal, Ltd, 2018 "This book has many innovations that make a welcome addition to the bookshelves of a wide range of pharmaceutical scientists. The effective use of figures and tables to summarize and clarify a wide range of issues is to be commended, as are the learning objectives at the start of the chapter coupled with the summary at the end providing a succinct way in understanding the objectives of the chapter and together with links to a website provides accessibility for all from the neophyte pharmacokineticist to the consultant physician. A book all in the Pharma industry should be aware of. "
— Int. J. of Pharmacokinetics, Howard M. Hill, ResolvPharma, 2018 "Overall, Introduction to Drug Disposition and Pharmacokinetics offers its readership an in-depth view of classic pharmacokinetic concepts. This book would be an excellent choice for a pharmacokinetics elective or as an adjunctive text for an introductory course. This book reviews a wide array of clinically relevant topics and encourages the reader to apply the knowledge gained to all medi-cations. A robust and varied amount of online material is provided to enhance understanding and encourage discussion. It is likely that all readers, novice or experienced pharmacists, would find value in this textbook."
— Currents in Pharmacy Teaching and Learning, Milena McLaughlin, Midwestern University Chicago College of Pharmacy, 2018 "In summary, this is an excellent textbook for students new to the field of pharmaceutics and medical, pharmacy, and veterinary students, particularly those who envision a career in drug development research in either academia or industry."
— Veterinary Pathology Review, John K. Amory, University of Washington, 2018

1
Introduction: Basic Concepts

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Learning objectives

This chapter was written for those unfamiliar with certain aspects of pharmacology and chemistry, including physical chemistry, and for those who feel a little revision would be helpful. By the end of the chapter the reader should be able to:

• use the Henderson–Hasselbalch equation to calculate the ionization of weak acids and bases
• plot concentration–time data to determine first‐order and zero‐order rate constants
• explain the effect of ionization on the partitioning of weak electrolytes between buffers and octanol.

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1.1 Introduction

Pharmacology can be divided into two major areas, pharmacodynamics (PD) – the study of what a drug does to the body – and pharmacokinetics (PK) – the study of what the body does to the drug; hardly rigorous definitions but they suffice. Drug disposition is a collective term used to describe drug absorption, distribution, metabolism and excretion whilst pharmacokinetics is the study of the rates of these processes. By subjecting the observed changes, for example in plasma concentrations as a function of time, to mathematical equations (models) pharmacokinetic parameters such as elimination half‐life (t_½), volume of distribution (V) and plasma clearance (CL) can be derived. Pharmacokinetic modelling is important for the:

• selection of the right drug for pharmaceutical development
• evaluation of drug delivery systems
• design of drug dosage regimens
• appropriate choice and use of drugs in the clinic.

A detailed knowledge of mathematics is not required to understand pharmacokinetics and it is certainly not necessary to be able to differentiate or integrate complex equations. The few examples in this book are standard differentials or integrals that can be quickly learnt if they are not known already. To understand the equations in this book requires little more than a basic knowledge of algebra, laws of indices and logarithms, a brief explanation of which can be found in Appendix 1. Furthermore, the astute reader will quickly realize that, although seemingly different, many equations take the same form, making learning easier. For example, drug binding to macromolecules, whether they be receptors, plasma proteins, transporters or enzymes, can be described using the same basic equation. Similarly, the equation describing the time course of formation and excretion of a drug metabolite is very much like that describing the plasma concentrations during the absorption and elimination of a drug.

The role of pharmacokinetics is illustrated in Figure 1.1. There is an optimum range of concentrations over which a drug has beneficial effects, but little or no toxicity – this range is the therapeutic range, sometimes referred to as the therapeutic window. There is a threshold concentration below which the drug in ineffective and a higher threshold above which adverse effects become problematic. If a single dose of a drug, for example aspi...

Table of contents

• Cover
• Title Page
• Table of Contents
• Preface
• Companion Website Directions
• 1 Introduction
• 2 Drug Administration and Distribution
• 3 Drug Metabolism and Excretion
• 4 Single-compartment Pharmacokinetic Models
• 5 Multiple-compartment and Non-compartment Pharmacokinetic Models
• 6 Kinetics of Metabolism and Excretion
• 7 Clearance, Protein Binding and Physiological Modelling
• 8 Quantitative Pharmacological Relationships
• 9 Pharmacokinetics of Large Molecules
• 10 Pharmacogenetics and Pharmacogenomics
• 11 Additional Factors Affecting Plasma Concentrations
• 12 Effects of Age and Disease on Drug Disposition
• 13 Drug Interactions and Toxicity
• 14 Perspectives and Prospects
• Appendix 1: Mathematical Concepts and the Trapezoidal Method
• Appendix 2: Dye Models to Teach Pharmacokinetics
• Appendix 3: Curve Fitting
• Appendix 4: Pharmacokinetic Simulations
• Index
• End User License Agreement