Drug Disposition and Pharmacokinetics E-Book

Stephen H. Curry

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 725

Veröffentlichungsjahr: 2011

Beschreibung

This is an authoritative, comprehensive book on the fate of drug molecules in the body, including implications for pharmacological and clinical effects. The text provides a unique, balanced approach, examining the specific physical and biological factors affecting the absorption, distribution, metabolism and excretion of drugs, together with mathematical assessment of the concentrations in plasma and body fluids. Understanding the equations requires little more than a basic knowledge of algebra, laws of indices and logarithms, and very simple calculus. A companion web site contains additional illustrations, further equations and numerous worked examples. Whilst this book has its roots in the highly acclaimed book of the same name, written by Stephen Curry nearly thirty years ago, it is essentially a new book having been restructured and largely rewritten. This readable and informative book is an invaluable resource for professionals and students needing to develop a rational approach to the investigation and application of drugs.

Leseprobe

Contents

Preface

About the Authors

Chapter 1: Chemical Introduction: Sources, Classification and Chemical Properties of Drugs

1.1 Introduction

1.2 Drug nomenclature and classification

1.3 Properties of molecules

1.4 Physicochemical interactions between drugs and other chemicals

1.5 Law of mass action

1.6 Ionization

1.7 Partition coefficients

1.8 Stereochemistry

Further reading and references

Chapter 2: Drug Administration and Distribution

2.1 Introduction

2.2 Drug transfer across biological membranes

2.3 Drug administration

2.4 Drug distribution

2.5 Plasma protein binding

2.6 Summary

References and further reading

Chapter 3: Drug Elimination

3.1 Introduction

3.2 Metabolism

3.3 Excretion

References and further reading

Chapter 4: Elementary Pharmacokinetics

4.1 Introduction

4.2 Single-compartment models

4.3 Non-linear kinetics

4.4 Relationship between dose, onset and duration of effect

4.5 Limitations of single-compartment models

4.6 Summary

References and further reading

Chapter 5: More Complex and Model Independent Pharmacokinetic Models

5.1 Introduction

5.2 Multiple compartment models

5.3 Curve fitting and choice of most appropriate model

5.4 Model independent approaches

5.5 Population pharmacokinetics

5.6 Summary

References and further reading

Chapter 6: Kinetics of Metabolism and Excretion

6.1 Introduction

6.2 Metabolite kinetics

6.3 Renal excretion

6.4 Excretion in faeces

References and further reading

Chapter 7: Further Consideration of Clearance, and Physiological Modelling

7.1 Introduction

7.2 Clearance in vitro (metabolic stability)

7.3 Clearance in vivo

7.4 Hepatic intrinsic clearance

7.5 In vitro to in vivo extrapolation

7.6 Limiting values of clearance

7.7 Safe and effective use of clearance

7.8 Physiological modelling

7.9 Inhomogeneity of plasma

References and further reading

Chapter 8: Drug Formulation: Bioavailability, Bioequivalence and Controlled-Release Preparations

8.1 Introduction

8.2 Dissolution

8.3 Systemic availability

8.4 Formulation factors affecting bioavailability

8.5 Bioequivalence

8.6 Controlled-release preparations

8.7 Conclusions

References and further reading

Chapter 9: Factors Affecting Plasma Concentrations

9.1 Introduction

9.2 Time of administration of dose

9.3 Food, diet and nutrition

9.4 Smoking

9.5 Circadian rhythms

9.6 Weight and obesity

9.7 Sex

9.8 Pregnancy

9.9 Ambulation, posture and exercise

References and further reading

Chapter 10: Pharmacogenetics and Pharmacogenomics

10.1 Introduction

10.2 Methods for the study of pharmacogenetics

10.3 N-acetyltransferase

10.4 Plasma cholinesterase

10.5 Cytochrome P450 polymorphisms

10.6 Alcohol dehydrogenase and acetaldehyde dehydrogenase

10.7 Thiopurine methyltransferase

10.8 Phase 2 enzymes

10.9 Transporters

10.10 Pharmacodynamic differences

References and further reading

Chapter 11: Developmental Pharmacology and Age-related Phenomena

11.1 Introduction

11.2 Scientific and regulatory environment in regard to younger and older patients

11.3 Terminology

11.4 Physiological and pharmacokinetic processes

11.5 Body surface area versus weight

11.6 Age groups

11.7 Further examples

Further reading and references

Chapter 12: Effects of Disease on Drug Disposition

12.1 Introduction

12.2 Gastrointestinal disorders and drug absorption

12.3 Congestive heart failure

12.4 Liver disease

12.5 Renal impairment

12.6 Thyroid disease

12.7 Summary

References and further reading

Chapter 13: Quantitative Pharmacological Relationships

13.1 Introduction

13.2 Concentration–effect relationships (dose–response curves)

13.3 The importance of relating dose–effect and time-action studies

References and further reading

Chapter 14: Pharmacokinetic/Pharmacodynamic Modelling: Simultaneous Measurement of Concentrations and Effect

14.1 Introduction

14.2 PK/PD modelling

References and further reading

Chapter 15: Extrapolation from Animals to Human Beings and Translational Science

15.1 Introduction

15.2 Allometric scaling

15.3 Dose-ranging versus microdosing studies

15.4 Statistical approaches

15.5 Translational science

References and further reading

Chapter 16: Peptides and Other Biological Molecules

16.1 Introduction

16.2 Chemical principles

16.3 Assay methods

16.4 Pharmacokinetic processes

16.5 Plasma kinetics and pharmacodynamics

16.6 Examples of particular interest

16.7 Conclusion

References and further reading

Chapter 17: Drug Interactions

17.1 Introduction

17.2 Terminology

17.3 Time action considerations

17.4 Interactions involving drug distribution and metabolism

17.5 Extent of drug interactions

17.6 Key examples

17.7 Further examples and mechanisms of a wide range of drug interactions

17.8 When are drug interactions important?

17.9 Desirable drug–drug interactions

17.10 Predicting the risk of future drug interactions with new chemical entities

References and further reading

Chapter 18: Drug Metabolism and Pharmacokinetics in Toxicology

18.1 Introduction

18.2 Terminology

18.3 Dose–response and time–action with special reference to toxicology

18.4 Safety studies in new drug discovery

18.5 Examples

References and further reading

Chapter 19: Drug Monitoring in Therapeutics

19.1 Introduction

19.2 General considerations

19.3 Specific examples

19.4 Dose adjustment

19.5 Summary

References and further reading

Appendix: Mathematical Concepts and the Trapezoidal Method

1 Algebra, variables and equations

2 Indices and powers

3 Logarithms

4 Calculus

Acknowledgements

Index

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Library of Congress Cataloging-in-Publication Data

Curry, Stephen H.Drug disposition and pharmacokinetics : from principles to applications /Stephen H. Curry and Robin Whelpton.p. ; cm.Includes bibliographical references and index.ISBN 978-0-470-68446-7 (cloth)1. Pharmacokinetics. 2. Biopharmaceutics. 3. Drugs–Metabolism. I.Whelpton, Robin. II. Title.[DNLM: 1. Pharmacokinetics. 2. Biopharmaceutics. 3. Pharmaceutical Preparations–metabolism.QV 38 C976da 2010]RM301.5.C863 2010615’.7–dc222010003126

A catalogue record for this book is available from the British Library.

Print ISBN: 978-0-470-684467ePDF ISBN 9780470665220oBook ISBN: 9780470665190

Preface

The origins of this book can be traced to a previous book with the same title written by one of us (S.H.C.) in 1974, second and third editions being published in 1977 and 1980. At the time, we were both in the early stages of what has become a very enjoyable career-long collaboration. Since that time newer approaches to the subject have been developed and many other books have been published. Mostly these have tended to be either very basic texts on pharmacokinetics, or weightier tomes, although some have been brief introductory texts, while yet others have concentrated on clinical applications. We have aimed to produce a book that takes the middle road, providing sufficient information and background to make it informative, clear, readable and enjoyable, without unnecessary complexity, maintaining the philosophy of the original Drug Disposition and Pharmacokinetics. Consequently, this book should be of benefit, in particular, to undergraduate and postgraduate students of science, including pharmacology, toxicology, medicinal chemistry and basic medical science, and students preparing for, and in, pre-professional programmes such as those in pharmacy, medicine and related disciplines, including dentistry and veterinary science, and environmental and public health. However, we are all life-long students, and thus this book is for anyone at any stage in his or her career wishing to learn about drug disposition and pharmacokinetics, that is, what happens to drug molecules in the body, but with strong emphasis on the pharmacological and clinical consequences of drug consumption, and so we expect our book to find readers among researchers, teachers and students in universities, in research institutes, in the professions, in industry, and in public laboratories employing toxicologists and environmental scientists in particular.

Clearly pharmacokinetics cannot be taught without recourse to mathematics. However, understanding the equations in this book requires little more than a basic knowledge of algebra, laws of indices and logarithms and very simple calculus. Anyone wishing to refresh his or her knowledge in these areas is recommended to read the Appendix. In a practical sense, it is important to be able to match standard equations to common graphical displays. There is little need in this context for the ability to derive complex equations. We believe in the old maxim, that a picture is worth a thousand words, and have noted that many of the principal pharmacokinetic relationships can be demonstrated empirically by the movement of dye into and out of volumes of water. We have used this approach to illustrate the validity of several models and further examples and colour plates can be found on the companion web site. This site also contains more mathematical examples, further equations and worked examples for readers who require them.

With few exceptions, we have adopted the system of pharmacokinetic symbols recommended by Aronson and colleagues (Eur J Clin Pharmacol 1988; 35: 1) where C represents concentration, A, is used for quantities or amounts, V for volumes of distribution, Q for flow rates, etc. First-order rate constants are either k or, if they are elimination rate constants, λ. Numbers have been used to designate compartments rather than letters (letters can lead to confusion, for example between plasma and peripheral) and for the exponents in multiple-compartment models. Thus, the variables for the biphasic decline of a two-compartment model are C1, C2, λ1 and λ2 rather than A, B, α and β, which may be familiar to some readers. It has not been possible to select a single convention for drug nomenclature. Rather, the names most likely to be familiar to readers around the world are used, and so we have leaned towards recommended International Non-proprietary Names (rINN). In most instances this should not cause problems for the majority of readers: cyclosporin, cyclosporine and ciclosporin clearly refer to the same drug. Where names are significantly different, alternatives are given in parentheses, e.g. pethidine (meperidine), and in the Index.

We have designed this book to be read from beginning to end in the order that we have presented the material. However, there is extensive cross-referral between sections and between chapters – this should aid those readers who prefer to ‘dip in,’ rather than start reading from Page 1. Thus, Chapter 1 is a brief presentation of the general chemical principles underlying the key mechanisms and processes described in the later chapters, effectively a mini-primer in medicinal chemistry. Drug disposition and pharmacokinetics is a discipline within the life sciences that depends entirely on these and other chemical principles. Chapters 2 and 3, which detail distribution and fate of drugs, are largely descriptive. Pharmacokinetic modelling of drug and metabolites, including more advanced concepts of clearance can be found in Chapters 4–7. Chapter 8 is devoted to bioavailability, particularly the influence of tablet formulation on concentrations of drugs in plasma and therefore on clinical outcome. The next four chapters (9–12) deal with what can be referred to as ‘special populations’ or ‘special considerations’: sex, disease, age and genetics in particular. The relationships between pharmacokinetics and pharmacological and clinical effects (PK-PD) are the topic of Chapters 13 and 14, whilst extrapolation from animals to human beings is considered in Chapter 15. The kinetics of macromolecules, including monoclonal antibodies, are considered in Chapter 16. The final chapters exemplify the importance of pharmacokinetics in three clinical areas, considering aspects of drug interactions, toxicity and therapeutic drug monitoring. Thus our sequence is from scientific preparation, through relevant science, to an introduction to clinical applications. The logical extension of the learning process in this area would be obtainable through one or more of the excellent texts available that focus on patient-care orientated pharmacokinetic research and practice.

Our examples come from our own experience, from literature of pivotal significance in the development of the subject, and from drugs that will be especially familiar to readers. Certain drugs stand out as demonstrating basic principles of widespread significance throughout the subject. They include propranolol, warfarin, digoxin, aspirin, theophylline and isoprenaline. It should be noted that these, and several other examples, can be considered as ‘old’ drugs. Some, indeed, such as isoprenaline and guanethidine, are obsolete as therapeutic agents, but still of paramount importance historically and as models. It was with these and other long-established drugs that principles of lasting significance were discovered. Of relevance to this is the fact that interest in this area of science undoubtedly existed among the ancients. More recently, Shakespeare referred to the risk–benefit ratio associated with alcohol consumption in Macbeth, and to the duration of action of the fantasy drug consumed by Juliet in Romeo and Juliet. Henry Bence Jones was probably the first to describe the rates of transfer of drugs between tissues, in work conducted in the 1860s, after he had developed assays for lithium and quinine. Awareness of the first-order removal of digoxin from the body originates from Gold et al. in the 1920s. However, it was in the 1930s that Widmark and Teorell first examined concentrations in blood. In the 1950s and 1960s, Brodie and Williams focused our interest on metabolism and metabolites, and then on quantitative pharmacology related to concentrations in blood. The big explosion of interest resulted from stirrings of pharmacokinetic thought in the colleges of pharmacy, and from the development of Clinical Pharmacology primarily in medical schools, in the 1960s, 1970s, and 1980s. It has been exciting to be associated with this dramatic development in medical science. Mathematical pharmacokinetics first gained prominence in relation to dosage form design, then to profiling of drugs in humans and control of clinical response, and, remarkably, only recently, in the process of new drug discovery.

We have not discussed bioanalysis, apart from a brief consideration of assay specificity in Chapter 19. However, it is important that the reader be aware that pharmacokinetic information can be no better than the quality of the concentration–time data provided. Thus, the pharmacokineticist should ensure that concentration data are from specific, precise and accurate assays, including their application to error-free timing of sample collections. Notes on other methods of drug investigation are to be found throughout the book, and readers interested in particular methods should be able to access relevant information through the index and references.

We hope that you enjoy this book. We thank our various students in London, Gainesville, Rochester, and too many other locations to mention, for their help in formulating our understanding of our readers’ needs in this subject area, and dedicate this book to them. We are immensely grateful to our publishers for their sage advice, and to our families for their support, tolerance and encouragement during the writing of this book.

Stephen H. Curry, Rochester, New York,Robin Whelpton, London,January 2010

About the Authors

Stephen Curry

Stephen has been Professor of Pharmacology at The London Hospital Medical College, Professor of Pharmaceutical Science at the University of Florida, and Adjunct Professor of Pharmacology and Physiology at the University of Rochester. He has also spent ten years with AstraZeneca and predecessor companies. He was honoured by the Faculty of Medicine of the University of London with the Doctor of Science Degree and is a Fellow of the Royal Pharmaceutical Society. He currently works in the field of technology transfer and translational science with early stage companies based on discoveries at the University of Rochester (PharmaNova) and Cornell University (ADispell). He can be contacted at www.stephenhcurry.com.

Robin Whelpton

After obtaining his first degree in Applied Chemistry, Robin joined the Department of Pharmacology and Therapeutics, London Hospital Medical College, University of London as research assistant to Professor Curry. Having obtained his PhD in pharmacology, he became lecturer and then senior lecturer before transferring to Queen Mary University of London, teaching pharmacology to preclinical medical students. He is currently a member of the School of Biological & Chemical Sciences and has a wealth of experience teaching drug distribution and pharmacokinetics to undergraduate and postgraduate students of medicine, pharmacology, biomedical sciences, pharmaceutical chemistry and forensic science.

1

Chemical Introduction: Sources, Classification and Chemical Properties of Drugs

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. 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 (t1/2), volume of distribution (V) and plasma clearance (CL) can be derived. Pharmacokinetic modelling is important for the:

Selection of the right drug for pharmaceutical developmentEvaluation of drug delivery systemsDesign of drug dosage regimensAppropriate choice and use of drugs in the clinic.

These points will be expanded in subsequent chapters.

A drug is a substance that is taken, or administered, to produce an effect, usually a desirable one. These effects are assessed as physiological, biochemical or behavioural changes. There are two major groups of chemicals studied and used as drugs. First, there is a group of pharmacologically interesting endogenous substances, for example acetylcholine, histamine and noradrenaline. Second, there are the nonendogenous, or ‘foreign’ chemicals (xenobiotics), which are mostly products of the laboratories of the pharmaceutical industry.

There are numerous ways in which drugs interact with physiological and biochemical process to elicit their responses. Many of these interactions are with macromolecules, frequently proteins and nucleic acids. Receptors are transmembrane proteins, with endogenous ligands typified by acetylcholine and noradrenaline (norepinephrine). Although substances may be present naturally in the body, they are considered drugs when they are administered, such as when adrenaline is injected to alleviate anaphylactic shock. Drugs can either mimic (agonists) or inhibit (antagonists) endogenous neurotransmitters. Salbutamol is a selective β2-agonist whereas propranolol is a non-selective β-blocker. Some receptors are ligand-gated ion channels, for example the cholinergic nicotinic receptor, which is competitively antagonized by (+)-tubocurarine. Enzymes, either membrane bound or soluble, can be inhibited – for example neostigmine inhibits acetylcholinesterase and aspirin inhibits cyclooxygenase. Other proteins that may be affected are voltage-gated (regulated) ion-channels – a typical one being voltage-gated sodium channels which are blocked by local anaesthetics such as lidocaine (lignocaine). Antimalarials, chloroquine, for example, intercalate in DNA. Some drugs work because of their physical presence – often affecting pH or osmolarity – for example antacids to reduce gastric acidity or sodium bicarbonate to increase urinary pH and thereby increase salicylate excretion (Section 3.3.1.5).

1.1.1 Source of drugs

Primitive therapeutics relied heavily on a variety of mixtures prepared from botanical and inorganic materials. The botanical materials included some extremely potent plant extracts, with actions for example on the brain, heart and gastrointestinal tract, and also some innocuous potions, which probably had little effect. The inorganic materials were generally alkalis, which did little more than partially neutralize gastric acidity. Potassium carbonate (potash, from wood fires) was chewed with coca leaves to hasten the release of cocaine. Inevitably, the relative importance of these materials has declined, but it should be recognized that about a dozen important drugs are still obtained, as purified chemical constituents, from botanical sources and that alkalis still have a very definite value in certain conditions. Amongst the botanical drugs, are the alkaloids: morphine is still obtained from opium, cocaine is still obtained from coca leaves, and atropine is still obtained from the deadly nightshade (belladonna). Although the pure compounds have been prepared synthetically in the laboratory, the most economical source is still the botanical material. Similarly, glycosides such as digoxin and digitoxin are still obtained from plants. These naturally occurring molecules often form the basis of semisynthetic derivatives – it being more cost-effective than synthesis de novo.

Similar considerations apply with some of the drugs of zoological origin. For instance, while the consumption of raw liver (an obviously zoological material) was once of great importance in the treatment of anaemia, modern treatment relies on cyanocobalamin, which occurs in raw liver, and on hydroxycobalamin, a semisynthetic analogue. Another zoological example is insulin, which was obtained from the pancreatic glands of pigs (porcine insulin) but can now be genetically engineered using a laboratory strain of Escherichia coli to give human insulin.

Most other naturally occurring drugs, including antibiotics (antimicrobial drugs of biological origin) and vitamins, are generally nowadays of known chemical structure, and although their synthesis in the laboratory is in most cases a chemical possibility, it is often more convenient and economical to extract them from natural sources. For the simpler molecules the converse may be true, for example chloramphenicol, first extracted from the bacterium, , is totally synthesized in the laboratory. For some antibiotics, penicillins and cephalosporins for example, the basic nucleus is of natural origin, but the modern drugs are semisynthetic modifications of the natural product.