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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Provides a timely update to a key textbook on human drug metabolism
The third edition of this comprehensive book covers basic concepts of teaching drug metabolism, starting from extreme clinical consequences to systems and mechanisms and toxicity. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its clinical impact.
Human Drug Metabolism, 3rd Edition begins by covering basic concepts such as clearance and bioavailability, and looks at the evolution of biotransformation, and how drugs fit into this carefully managed biological environment. More information on how cytochrome P450s function and how they are modulated at the sub-cellular level is offered in this new edition. The book also introduces helpful concepts for those struggling with the relationship of pharmacology to physiology, as well as the inhibition of biotransformational activity. Recent advances in knowledge of a number of other metabolizing systems are covered, including glucuronidation and sulphation, along with the main drug transporters. Also, themes from the last edition are developed in an attempt to chart the progress of personalized medicine from concepts towards practical inclusion in routine therapeutics. The last chapter focuses on our understanding of how and why drugs injure us, both in predictable and unpredictable ways. Appendix A highlights some practical approaches employed in both drug metabolism research and drug discovery, whilst Appendix B outlines the metabolism of some drugs of abuse. Appendix C advises on formal examination preparation and Appendix D lists some substrates, inducers and inhibitors of the major human cytochrome P450s.
- Fully updated to reflect advances in the scientific field of drug metabolism and its clinical impact
- Reflects refinements in the author's teaching method, particularly with respect to helping students understand biological systems and how they operate
- Illustrates the growing relationship between drug metabolism and personalized medicine
- Includes recent developments in drug discovery, genomics, and stem cell technologies
Human Drug Metabolism, 3rd Edition is an excellent book for advanced undergraduate and graduate students in molecular biology, biochemistry, pharmacology, pharmacy, and toxicology. It will also appeal to professionals interested in an introduction to this field, or who want to learn more about these bench-to-bedside topics to apply it to their practice.
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Table of Contents
Cover
Preface
1 Introduction
1.1 Therapeutic window
1.2 Consequences of drug concentration changes
1.3 Clearance
1.4 First pass and drug extraction
1.5 First pass and plasma drug levels
1.6 Drug and xenobiotic metabolism
References
2 Drug Biotransformational Systems – Origins and Aims
2.1 Biotransforming enzymes
2.2 Threat of lipophilic hydrocarbons
2.3 Cell communication
2.4 False signal molecules: bioprotection
2.5 Sites of biotransforming enzymes
2.6 Biotransformation and xenobiotic cell entry
References
3 How Oxidative Systems Metabolise Substrates
3.1 Introduction
3.2 Capture of lipophilic molecules
3.3 Cytochrome P450s: nomenclature and methods of study
3.4 CYPs: main and associated structures
3.5 Human CYP families and their regulation
3.6 Main human CYP families
3.7 Cytochrome P450 catalytic cycle
3.8 Flavin monooxygenases (FMOs)
3.9 How CYP isoforms operate
in vivo
3.10 Aromatic ring hydroxylation
3.11 Alkyl oxidations
3.12 Rearrangement reactions
3.13 Other oxidation processes
3.14 Control of CYP metabolic function
References
4 Induction of Cytochrome P450 Systems
4.1 Introduction
4.2 Causes of accelerated clearance
4.3 Enzyme induction
4.4 Mechanisms of enzyme induction
4.5 Induction: general clinical aspects
4.6 Induction: practical considerations
4.7 Induction vs. inhibition: which ‘wins’?
4.8 Induction: long‐term impact
References
5 Cytochrome P450 Inhibition
5.1 Introduction
5.2 Inhibition of metabolism: general aspects
5.3 Mechanisms of reversible inhibition
5.4 Mechanisms of irreversible inhibition
5.5 Clinical consequences of irreversible inhibition
5.6 Cell transport systems and inhibition
5.7 Major clinical consequences of inhibition of drug clearance
5.8 Use of inhibitors for positive clinical intervention
5.9 Summary
References
6 Conjugation and Transport Processes
6.1 Introduction
6.2 Glucuronidation
6.3 Sulphonation
6.4 The GSH system
6.5 Glutathione S‐transferases
6.6 Epoxide hydrolases
6.7 Acetylation
6.8 Methylation
6.9 Esterases/amidases
6.10 Amino acid conjugation (mainly glycine)
6.11 Phase III transport processes
6.12 Biotransformation: integration of processes
References
7 Factors Affecting Drug Metabolism
7.1 Introduction
7.2 Genetic polymorphisms
7.3 Effects of age on drug metabolism
7.4 Effects of diet on drug metabolism
7.5 Gender effects
7.6 Smoking
7.7 Effects of ethanol on drug metabolism
7.8 Artificial livers
7.9 Effects of disease on drug metabolism
7.10 Summary
References
8 Role of Metabolism in Drug Toxicity
8.1 Adverse drug reactions: definitions
8.2 Predictable drug adverse effects: type A
8.3 Unpredictable drug adverse effects: type B
8.4 Nature of drug‐mediated immune responses
8.5 Type B3 reactions: role of metabolism in cancer
8.6 Summary of biotransformational toxicity
References
Appendix A: Appendix ADrug Metabolism in Drug DiscoveryDrug Metabolism in Drug Discovery
A.1 The pharmaceutical industry
A.2 Drug design and biotransformation: strategies
A.3 Animal and human experimental models: strategies
A.4
In vitro
metabolism platforms and methods
A.5 Animal model developments in drug metabolism
A.6 Toxicological assays
A.7
In silico
approaches
A.8 Summary
References
Appendix B: Appendix BMetabolism of Major Illicit DrugsMetabolism of Major Illicit Drugs
B.1 Introduction
B.2 Opiates
B.3 Cocaine
B.4 Hallucinogens
B.5 Amphetamine derivatives
B.6 Cannabis
B.7 Dissociative anaesthetics
B.8 Charlie Don’t Surf!
137
References
Appendix C: Appendix CExamination TechniquesExamination Techniques
C.1 Introduction
C.2 A first‐class answer
C.3 Preparation
C.4 The day of reckoning
C.5 Foreign students
Appendix D: Appendix DSummary of Major CYP Isoforms and Their Substrates, Inhibitors, and InducersSummary of Major CYP Isoforms and Their Substrates, Inhibitors, and Inducers
Index
End User License Agreement
List of Tables
Chapter 8
Table 8.1 Time frame and clinical markers of paracetamol toxicity
Table 8.2 The relationship between the stability of aromatic hydroxylamines a...
List of Illustrations
Chapter 1
Figure 1.1 The therapeutic window, where drug concentrations should be maint...
Figure 1.2 Consequences of drug interactions in terms of metabolic changes a...
Figure 1.3 The first pass of an orally dosed highly cleared drug showing the...
Chapter 2
Figure 2.1 The lipophilicity (oil loving) and hydrophilicity (water loving) ...
Figure 2.2 Various functions of biotransformational enzymes, from assembly o...
Figure 2.3 The hepatocytes can simultaneously metabolize xenobiotics in the ...
Figure 2.4 Hepatocyte transporters take up drugs from the hepatic portal and...
Chapter 3
Figure 3.1 Location of CYP enzymes and their REDOX partners, cytochrome
b
5
a...
Figure 3.2 Main structural features of ferriprotoporphyrin‐9, showing the ir...
Figure 3.3 Diagram of CYP homotropic and heterotropic substrate binding. CYP...
Figure 3.4 Position of CYP reductase (POR) in relation to CYP enzyme and the...
Figure 3.5 Direction of electron flow in P450 oxidoreductase (POR) supply of...
Figure 3.6 Cytochrome
b
5
and POR’s roles in supplying reducing power to CYP‐...
Figure 3.7 Summary of the local pre‐and post‐translational modulation of CYP...
Figure 3.8 Simplified scheme of cytochrome P450 operations
Figure 3.9 Generic structure of a flavin monooxygenase (FMO)
Figure 3.10 Process of flavin monooxygenase catalysis: a–c outlines the firs...
Figure 3.11 Some aromatic hydrocarbon molecules
Figure 3.12 Main pathways of benzene hydroxylation
Figure 3.13 Omega and omega minus one carbon oxidation of aliphatic saturate...
Figure 3.14 Formation of unsaturated bonds from a saturated starting point
Figure 3.15 Metabolism of unsaturated alkyl groups
Figure 3.16 Oxidation of hexane to hexanols
Figure 3.17 Formation of the neurotoxin 2,5 hexanedione by CYP oxidations
Figure 3.18 Rearrangement reactions caused by the CYP‐mediated oxidation of ...
Figure 3.19 Metabolism of terfenadine: essentially the same oxidation reacti...
Figure 3.20 Pathways of CYP‐mediated N‐oxidation and N‐dealkylation
Figure 3.21 Sulphoxide and N‐oxide formation with chlorpromazine, formed by ...
Figure 3.22 Oxidative deamination of amphetamine
Figure 3.23 Removal of halides through an unstable alcohol intermediate
Figure 3.24 Primary amine oxidation
Chapter 4
Figure 4.1 Physiological regulatory triangle.
Mission control
could be a gen...
Figure 4.2 Physiological regulatory ‘triangle’ where ‘mission control’ recei...
Figure 4.3 Basic mechanism of CYP1A1 and 1A2 induction: the AhR receptor bin...
Figure 4.4 (a) Constitutive androstane receptor (CAR)‐mediated control of CY...
Figure 4.5 Mechanism of CYP3A induction through the pregnane X receptor (PXR...
Figure 4.6 CYP2E1 induction: this CYP is not controlled by nuclear receptors...
Figure 4.7 Generic summary of CYP induction. With the exception of CYP2E1 (F...
Chapter 5
Figure 5.1 Main types of enzyme inhibition that apply to CYP isoforms
Figure 5.2 Scheme of normal substrate CYP binding (left) and mechanism‐based...
Figure 5.3 The impact of a hERG receptor‐inhibiting drug on the QT interval,...
Chapter 6
Figure 6.1 Scheme showing the approximate position of glucuronyl transferase...
Figure 6.2 Process scheme for the preparation of glucose to UDP glucuronic a...
Figure 6.3 Formation of acyl glucuronides from drugs containing a carboxylic...
Figure 6.4
S
cheme for glucuronidation of aromatic amines and hydroxylamines...
Figure 6.5 Control of UGT1A1 expression: the multi‐site gtPBREM allows the i...
Figure 6.6 Basic reactions of sulphotransferases
Figure 6.7 The GSH maintenance system in man
Figure 6.8 A typical GST catalysed reaction of GSH with a potentially reacti...
Figure 6.9 The nrf2 system is intended to respond to electrophiles, which pr...
Figure 6.10 A typical microsomal epoxide hydrolase reaction: formation of ca...
Figure 6.11 Mechanism of action of epoxide hydrolase in the conversion of a ...
Figure 6.12 Esterase and amidase reaction sequences
Figure 6.13 A scheme showing some major biotransformational systems operatin...
Chapter 7
Figure 7.1 Basic scheme for sulphonamide metabolism and how adverse reaction...
Figure 7.2 The role of acetylation in dapsone metabolism
Figure 7.3 Acetylation and isoniazid metabolism
Figure 7.4 Scheme of the role of TPMT polymorphisms in the metabolism of S‐m...
Figure 7.5 Generalised scheme of factors that influence drug metabolism, lea...
Chapter 8
Figure 8.1 Summary of reversible (type A) and irreversible (type B) drug eff...
Figure 8.2 Basic process of methaemoglobin formation in the human erythrocyt...
Figure 8.3 Production of various methaemoglobin‐forming species from dapsone...
Figure 8.4 Main consequences of reactive species formation due to xenobiotic...
Figure 8.5 Main features of paracetamol metabolism. Aside from the toxic NAP...
Figure 8.6 Extracellular and intracellular antigen processing
Figure 8.7 The hapten hypothesis as it might apply to CYP‐mediated reactive ...
Figure 8.8 Aside from the hapten hypothesis, there are other competing hypot...
Figure 8.9 Stages of oxidation and reduction of aromatic amines
Figure 8.10 Some major metabolites of aromatic amines and their possible rol...
Figure 8.11 Final formation of aromatic amine‐derived carcinogenic metabolit...
Figure 8.12 Processes of possible activation of 3‐nitrobenzanthrone by reduc...
Figure 8.13 Acrylamide and its paths of human toxicity
Figure 8.14 Structure of aflatoxin B1 and its carcinogenic and non‐genotoxic...
Figure 8.15 The links between drug metabolism, formation of active species, ...
Appendix A
Figure A.1 Broad summary of the role of techniques based on drug metabolism ...
Appendix B
Figure B.1 Structures of some morphine‐based and synthetic opiates
Figure B.2 Dual, sequential N‐demethylation of methadone to inactive product...
Figure B.3 Cocaine metabolism, showing the role of CYP3A4 in demethylation (...
Figure B.4 Formation of cocaethylene by esterification with ethanol and the ...
Figure B.5 Metabolism of LSD: formation of lysergic acid ethylamide (LSE), n...
Figure B.6 Some routes of dimethyltryptamine derivative clearance leading to...
Figure B.7 Methylenedioxy amphetamine derivatives: MDMA (methylenedioxymethy...
Figure B.8 Metabolism of MDMA: the main route of clearance is initially via ...
Figure B.9 Various amphetamine‐like derivatives, alongside dopamine
Figure B.10 Structures of dopamine, d‐amphetamine, N‐benzylpiperazine (BZP) ...
Figure B.11 The main active constituents of
Cannabis
variants, ∆
8
‐ and ∆
9
‐TH...
Figure B.12 Synthetic cannabinoid derivatives found in ‘Spice’ shown alongsi...
Figure B.13 Major metabolites of PCP in man; CYP2B6 K262R cannot form the re...
Figure B.14 Structure of ketamine and its major demethylated derivative nork...
Guide
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Human Drug Metabolism
Third Edition
Michael D. Coleman
Birmingham, UK
This third edition first published 2020© 2020 John Wiley & Sons, Inc.
Edition HistoryJohn Wiley & Sons, Ltd (1e, 2005); John Wiley & Sons, Ltd (2e, 2010)
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
The right of Michael D. Coleman to be identified as the author of this work has been asserted in accordance with law.
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Library of Congress Cataloging‐in‐Publication Data
Names: Coleman, Michael D, author.Title: Human drug metabolism / Michael D. Coleman.Description: Third edition. | Hoboken, NJ : Wiley‐Blackwell, 2020. | Includes bibliographical references and index.Identifiers: LCCN 2019032038 (print) | LCCN 2019032039 (ebook) | ISBN 9781119458562 (paperback) | ISBN 9781119458609 (adobe pdf) | ISBN 9781119458616 (epub)Subjects: LCSH: Drugs–Metabolism. | Xenobiotics–Psychological aspects.Classification: LCC RM301.55 .C65 2020 (print) | LCC RM301.55 (ebook) | DDC 615.1–dc23LC record available at https://lccn.loc.gov/2019032038LC ebook record available at https://lccn.loc.gov/2019032039
Cover Design: WileyCover Images: Dapsone antibacterial drug molecule © MOLEKUUL/science source Author Photo: Courtesy of Michael D. Coleman
For Mark, Carol, and Devon
Preface
In the spring of 1986 in a crackly transatlantic telephone conversation, I recall discussing my impending postdoctoral work at the Walter Reed Army Institute of Research in Washington D.C., with Dr Melvin H. Heiffer, then Chief of the Pharmacology Section. I distinctly remember him saying that I could look forward to ‘a beautiful adventure in Pharmacology’. Whilst it started well, the dream of working in the United States darkened somewhat after a few months as I realised the true depth and resonance of a phrase I used to see as I passed by, which was set in stone on the front of the now demolished Stanley Hospital in Liverpool: ‘I was sick and ye visited me’.
However, a year or so after the conversation with Mel, I remember experiencing an intense epiphany of gratitude whilst cruising down the middle lane of a busy I‐95 near Bethesda, Maryland, in the ’69 Dodge you can see on the back cover. Like self‐effacing molecular superheroes, rifampicin, isoniazid, ethambutol, and streptomycin, were in the process of returning to me the life I would have inevitably lost had I been born in another age. Indeed, our more distant ancestors would have regarded the transformative power of many of the latest therapeutic approaches as something akin to magic.
Unfortunately, we know the reality of drug therapy is not always quite as restorative, as not only does it sometimes fail, it can also cause serious harm. Pharmacology is a large subject area, and drug metabolism is just a component of it. However, I hope that this book illustrates the importance of some knowledge of drug biotransformation in the process of realising the full and dazzling potential of many modern drugs whilst minimizing adverse reactions as far as humanly possible.
This is the third edition of this book, and I have tried to improve and update the text to reflect the advances in drug metabolism in the decade since the last edition. The basic outline of the book has not changed, but the text is now referenced, using a modified Vancouver style, with each citation numbered consecutively and then listed at the end of each chapter. It is not as densely referenced as a scientific review paper might be, but it does provide sources that can act as channels to a wider understanding of each covered area. I hope that this will make the book more useful and practical as a starting point in this subject, without losing the approachability of the text. Whether I have achieved this aim remains to be seen, but the intention is to provide all those engaged in the study and use of drugs at every level, with insights into how knowledge of drug metabolism can help optimize therapeutics, whilst minimizing adverse reactions.
More than ever, therapeutics is a complex joint enterprise where many participants contribute their expertise towards the welfare of the patient. So the book is intended to be accessible to everyone who has ambitions to be involved in every stage of a drug’s life, from inception to clinical use and perhaps even withdrawal. Hence, the book is intended to reach students, practitioners, health‐care professionals, and scientists, providing an accessible source of information and reference material for further study.
Chapter 1 as before covers some basic concepts such as clearance and bioavailability. Chapter 2 looks at the evolution of biotransformation and how it both serves and protects us. How drugs fit into this carefully managed biological environment and what this means for drug action is examined from Chapter 3 onwards. In this edition, more is now included on how cytochrome P450s function and how they are modulated at the sub‐cellular level, as well as the usual list of the basic oxidations, reductions, and hydrolyses that are necessary for any basic text in drug metabolism.
Chapter 4 opens with some concepts that I hope will help those who might struggle with the relationship of Pharmacology to Physiology. The themes briefly explored include how biological systems control themselves at the most basic level and how to map this concept onto normal and aberrant physiological processes, followed by the effect of pharmacological intervention. It also provides some very basic perspectives on why drugs sometimes fall short of expectations in terms of efficacy. This echoes a theme of Chapter 2, in relation to endocrine disruption, where living systems must battle a sea of ‘hostile’ chemicals to preserve their identity, purpose, and activity, and the essential prerequisite is to detect and control endogenous and exogenous chemicals, who are, respectively, our molecular servants and possible threats to our well‐being. Chapter 4 also outlines the cellular systems that act on the information received in these molecules, including drugs and what this means for drug efficacy. In this edition, I have tried to reflect the recent increased understanding of biosensors such as PXR and how they influence so many endogenous functions, as well as their role in disease.
Chapter 5 focusses on inhibition of biotransformational activity, both in regard to the main mechanisms involved, classes of drug, and chemical inhibitors and finally what this means clinically. It provides an opportunity to discuss drug classes such as the azoles and antidepressants in a wider clinical, pharmacological, and sometimes even a social context.
Chapter 6 outlines what is still termed ‘Phase II’ conjugative and related biotransforming reactions. It reflects recent advances in knowledge in a number of enzyme systems, such as in glucuronidation, sulphation, and in some of the methylating enzyme systems and their clinical significance.
Chapter 7 develops themes from the second edition, as it attempts to chart the progress of personalised medicine from concepts towards practical inclusion in routine therapeutics. In the last decade, some extremely important advances have been made in terms of customising medicines to ethnic groups and the technology to determine genetic enzymatic identity has literally reached a retail outlet near you, in some cases. However, some of the obstacles that remain in the path towards personalized medicine are discussed. Other aspects of what the patient brings to the therapeutic situation are also covered, in relation to age, gender, and personal habits in this chapter.
Chapter 8 focusses on our understanding of how and why drugs injure us, both in predictable and unpredictable ways. The role of the immune system in drug toxicity is now better understood than a decade ago, yet still reactions linked to drug‐immune problems can be as life‐threatening as they are unpredictable. However, advances in pharmacogenetics have brought us to the point where we can now warn whole ethnic groups of people not to take certain drugs, which is already saving lives and preventing much suffering.
Appendix A is intended to provide a perspective on how knowledge of biotransformation is an integral part of drug development and how it is feeding into the design as well as the eventual applications of particular drugs. Some of the main experimental models are explored within the context of the business and scientific models the pharmaceutical industry currently uses. Appendix B, has been expanded to look at the less‐than‐beautiful adventures in Pharmacology that some drugs of abuse are bringing to users around the world over the past decade, as well as some information on their effects, disposition, and routes of metabolism as far as they are known. Appendix C as before is intended to assist students to marshal and focus their inner Einstein towards examinations, and finally, Appendix D provides a brief list of some major drugs and their assigned major biotransforming enzymes.
Once again, I would like to thank my mother, Jean, for her encouragement and my wife, Clare, for her forbearance when I spent seemingly ever‐increasing amounts of time on this project. Unfortunately, no matter how much effort is devoted to a task, there are always errors and omissions. However, in memory of Mel Heiffer, whose courage matched his eloquence, I hope that this book makes your own personal adventure in Pharmacology perhaps just a shade more beautiful.
Michael D. Coleman,Bournville, Birmingham
1Introduction
1.1 Therapeutic window
1.1.1 Introduction
It has been said that if a drug has no side effects, then it is unlikely to work. Drug therapy labours under the fundamental problem that usually every single cell in the body has to be treated just to exert a beneficial effect on a small group of cells, perhaps in one tissue. Although drug‐targeting technology is improving rapidly, most of us who take an oral dose are still faced with the problem that the vast majority of our cells are being unnecessarily exposed to an agent that at best will have no effect, but at worst will exert many unwanted effects. Essentially, all drug treatment is really a compromise between positive and negative effects in the patient. The process of drug development weeds out agents that have seriously negative actions and usually releases onto the market drugs that may have a profile of side effects, but these are relatively minor within a set concentration range where the drug’s pharmacological action is most effective. This range, or therapeutic window, is rather variable, but it will give some indication of the most ‘efficient’ drug concentration. This effectively means the most beneficial pharmacodynamic effects for the minimum side effects.
The therapeutic window (Figure 1.1) may or may not correspond exactly to active tissue concentrations, but it is a useful guideline as to whether drug levels are within the appropriate range. Sometimes, a drug is given once only and it is necessary for drug levels to be within the therapeutic window for a relatively brief period, perhaps when paracetamol (acetaminophen) is taken as a mild analgesic. However, the majority of drugs require repeated dosing in time periods that range from a few days for a course of antibiotics, to many years for anti‐hypertensives and antithyroid drugs. During repeated intermediate and long‐term dosing, drug levels may move below or above the therapeutic window due to events such as patient illness, changes in diet, or co‐administration of other drugs. Below the lowest concentration of the window, it is likely that the drug will fail to work, as the pharmacodynamic effect will be too slight to be beneficial. If the drug concentration climbs above the therapeutic window, an intensification of the drug’s intended and unintended (off‐target) pharmacodynamic actions will occur. If drug levels continue to rise, significant adverse effects may ensue which can lead to distress, incapacitation or even death. To some extent, every patient has a unique therapeutic window for each drug they take, as there is such huge variation in our pharmacodynamic drug sensitivities. This book is concerned with what systems influence how long a drug stays in our bodies.
Figure 1.1 The therapeutic window, where drug concentrations should be maintained for adequate therapeutic effect, without either accumulation (drug toxicity) or disappearance (drug failure). Such is human variation that our personal therapeutic windows are effectively unique for every drug we take
Whether drug concentrations stay in the therapeutic window is obviously related to how quickly the agent enters the blood and tissues prior to its removal. When a drug is given intravenously, there is no barrier to entry, so drug input may be easily and quickly adjusted to correspond with the rate of removal within the therapeutic window. This is known as steady state, which is the main objective of therapeutics. The majority of drug use is by other routes such as oral or intramuscular rather than intravenous, so there will be a considerable time lag as the drug is absorbed from either the gastrointestinal tract (GIT) or the muscle, so achieving drug levels within the therapeutic window is a slower, more ‘hit and miss’ process. The result from repeated oral dosing is a rather crude peak/trough pulsing, or ‘sawtooth’ effect, which you can see in Figure 1.1. This should be adequate, provided that the peaks and troughs remain within the confines of the therapeutic window.
1.1.2 Therapeutic index
Drugs vary enormously in their toxicity and indeed, the word toxicity has a number of potential meanings. Broadly, it is usually accepted that toxicity equates with harm to the individual. However, ‘harm’ could describe a range of impacts to the individual from mild to severe, or reversible to irreversible, in any given time frame. There is a detailed discussion on what constitutes toxicity in Chapter 8 (sections 2 and 3), but for the meantime, the broad process of harm might begin with supra‐therapeutic ‘pharmacological’ reversible effects, progressing through to irreversible, damaging toxic effects with ascending dosage. Indeed, the concentrations at which one drug might cause potentially harmful or even lethal effects might be 10 to 1000 times lower than a much less toxic drug. A convenient measure for this is the therapeutic index (TI). This has been defined as the ratio between the lethal or toxic dose and the effective dose that shows the normal range of pharmacological effect.
In practice, a drug like lithium, for example, is listed as having a narrow TI if there is twofold or less difference between the lethal and effective doses, or a twofold difference in the minimum toxic and minimum effective concentrations. Back in the 1960s, many drugs in common use had narrow TIs, such as barbiturates, that could be toxic at relatively low levels. Since the 1970s, the drug industry has aimed to replace this type of drug with agents with much wider TIs. This is particularly noticeable in drugs used for depression. The risk of suicide is likely to be high in a condition that takes some time (often several weeks) to respond to therapy. Indeed, when tricyclic antidepressants (TCAs) were the main treatment option, these relatively narrow TI drugs could be used by the patient to end their lives. Fortunately, more modern drugs such as the SSRIs (selective serotonin reuptake inhibitors) have much wider TIs, so the risk of the patient using the drugs for a suicide attempt is greatly diminished. However, many drugs (including the TCAs to a limited extent) remain in use that have narrow or relatively narrow TIs (e.g. phenytoin, carbamazepine, valproate, warfarin). Therefore, the consequences of accumulation of these drugs are much worse and happen more quickly than drugs with wide TIs.
1.1.3 Changes in dosage
If the dosage exceeds the rate of the drug’s removal, then clearly drug levels will accumulate and depart from the therapeutic window towards potential harm to the patient. If the drug dosage is too low, levels will fall below the lowest threshold of the window and the drug will fail to work. If a patient continues to respond well at the same oral dose, then this is effectively the oral version of steady state. So, theoretically, the drug should remain in its therapeutic window at this ‘correct’ dosage for as long as therapy is necessary unless other factors change this situation.
1.1.4 Changes in rate of removal
The patient may continue to take the drug at the correct dosage, but at some point drug levels may drop out of, or alternatively exceed, the therapeutic window. This could be linked with redistribution of the drug between bodily areas such as plasma and a particular organ, or protein binding might fluctuate; however, provided dosage is unchanged, significant fluctuation in drug levels within the therapeutic window will be due to change in the rate of removal and/or inactivation of the drug by active bodily processes.
1.2 Consequences of drug concentration changes
If there are large changes in the rate of removal of a drug, then this can lead in extremis to severe problems in the outcome of the patient’s treatment: the first is drug failure, whilst the second is the drug causing harm (Figure 1.2). These extremes and indeed all drug effects are directly related to the blood concentrations of the agent in question.
1.2.1 Drug failure
Although it might take nearly a decade and huge sums of money to develop a drug that is highly effective in the vast majority of patients, the drug can only exert an effect if it reaches its intended target in sufficient concentration. Assuming that the patient has taken the drug, there may be many reasons why sufficient systemic concentrations cannot be reached. Drug absorption may have been poor, or it may have been bound to proteins or removed from the target cells so quickly it cannot work. This situation of drug ‘failure’ might occur after treatment has first appeared to be successful, where a patient was stabilized on a particular drug regimen, which then fails due to the addition of another drug or chemical to the regimen. The second drug or chemical causes the failure by accelerating the removal of the first from the patient’s system, so drug levels are then too low to be effective. The clinical consequences of drug failure can be serious for both for the patient and the community. In the treatment of epilepsy, the loss of effective control of the patient’s seizures could lead to injury to themselves or others. The failure of a contraceptive drug would lead to an unwanted pregnancy and the failure of an antipsychotic drug could mean hospitalization for a patient at the very least. For the community, when the clearance of an antibiotic or antiparasitic drug is accelerated, this causes drug levels to fall below the minimum inhibitory concentration, thus selecting drug‐resistant mutants of the infection. Therapeutic drug failure is usually a gradual process, where the time frame may be many days before the problem is detected (Figure 1.2).
Figure 1.2 Consequences of drug interactions in terms of metabolic changes and their effects on drug failure and toxicity
1.2.2 Drug toxicity
If a drug accumulates for any reason, either by overdose or by a failure of drug removal, then serious adverse reactions can potentially result. A reduction in the rate of removal of the drug from a system (often due to administration of another drug), will lead to drug accumulation. Harm to the patient may occur through the gradual intensification of a drug’s therapeutic action, which progresses to off‐target effects. The situation may even progress to irreversible damage to tissue or a whole organ system. For example, if the immunosuppressive cyclosporine is allowed to accumulate, severe renal toxicity can lead to organ failure. Excessive levels of anticonvulsant and antipsychotic drugs cause confusion and drowsiness, whilst the accumulation of the now‐withdrawn antihistamine terfenadine can lead to lethal cardiac arrhythmias. In contrast to drug failure, drug toxicity may occur much more rapidly, often within hours rather than days.
1.3 Clearance
1.3.1 Definitions
The consequences for the patient when drug concentrations either fall below the therapeutic window or exceed it can be life threatening. The rate of removal of the drug from the body determines whether it will disappear from, or accumulate in, the patient’s blood. A concept has been devised to understand and measure rate of removal; this is known as clearance. This term does not mean that the drug disappears or is ‘cleared’ instantly. The definition of clearance is an important one that should be retained:
Clearance is the removal of drug by all processes from the biological system
.
A more advanced definition could be taken as:
A volume of fluid (plasma, blood or total body fluid) from which a drug is
irreversibly
removed in unit time
.
Clearance is measured in millilitres of blood or plasma per min (or litres per hour) and is often taken to mean the ‘clearance’ of the drug’s pharmacological effectiveness, which resides in its chemical structure. Once the drug has been metabolized, or ‘biotransformed’, even though only a relatively trivial change may have been made in the structure, it is no longer as it was, and products of metabolism, or metabolites as they are known, often exert less or even no therapeutic effect. An exception would be a pro‐drug, such as the antithrombotic agent clopidogrel, which is inactive unless it is metabolised to its active form (Chapter 7.2.2).
Whether or not a metabolite retains some therapeutic effect, it will usually be removed from the cell faster than the parent drug and will eventually be excreted in urine and faeces. There are exceptions where metabolites are comparable in pharmacological effect with the parent drug (some tricyclic antidepressants, such as desipramine and morphine‐6‐glucuronide). In addition, there are metabolites that are strangely even less soluble in water and harder to excrete than the parent compound (acetylated sulphonamides), but in general, the main measure of clearance is known as total body clearance, or sometimes, systemic clearance:
This can be regarded as the sum of all the processes that can clear the drug. Effectively, this means the sum of the liver and kidney contributions to drug clearance, although the gut, lung and other organs can make a significant contribution. For drugs like atenolol or gabapentin, which unusually do not undergo any hepatic metabolism, or indeed metabolism by any other organ, it is possible to say that:
So renal clearance is the only route of clearance for these drugs, in fact it is 100% of clearance. For paracetamol and for most other drugs, total body clearance is a combination of hepatic and renal clearances:
For ethanol, you may know there are several routes of clearance, including hepatic, renal, and the lung, as breath tests are a well‐established indicator of blood concentrations.
Once it is clear what clearance means, then the next step is to consider how clearance occurs.
1.3.2 Clearance and elimination
In absolute terms, to clear something away is to get rid of it, to remove it physically from a system. The kidneys are mostly responsible for this absolute removal, known as elimination. As we will see, the whole of the biotransforming system as it applies to xenobiotic (foreign) and endobiotic (such as our hormones) compounds could be said to have evolved around the strengths and limitations of our kidneys. Large chemical entities like proteins, cannot normally be filtered from blood by the kidneys, but they do remove the majority of smaller chemicals, depending on size, charge, and water solubility. Necessary nutrients are actively reclaimed before the soluble filtrate waste eventually reaches the collecting tubules that lead to the ureter and thence to the bladder. However, as the kidney is a lipophilic (oil‐loving) organ, even if it filters lipophilic drugs or toxins, these are likely to leave the urine in the collecting tubules, enter the surrounding lipophilic tissues, and return to the blood. So the kidney is not actually capable of eliminating lipophilic chemicals or anything that is not soluble in water.
1.3.3 Biotransformation prior to elimination
It is clear that lipophilic agents must be made water soluble enough to be cleared by the kidney, which means they must be structurally altered, which is in turn achieved through biotransformation. The organs that have the most significant roles in this activity are the liver, gut, kidney, and lung. These organs must extract a drug from the circulation, biotransform it, then return the hopefully water‐soluble metabolite to the blood for the kidney to remove. Of the biotransforming organs, the liver has the greatest role in this process and like the kidney, it can metabolize and physically remove some metabolic products from the circulation. This happens through the excretion of higher molecular weight (350–500 Daltons) drugs and metabolites into bile, where they travel through the gut to be either further metabolized by the gut microbiota, or eventually eliminated in faeces. The microbiota can have very profound effects on the disposition of a drug and its metabolites, which is discussed in Chapter 6 (section 6.2.12).
1.3.4 Intrinsic clearance
The liver and the other biotransforming organs all possess an impressive and diverse array of enzymatic systems to biotransform drugs, toxins, and other chemical entities to more water‐soluble products. However, the ability of any biotransforming organ to metabolize a given drug can depend on several factors.
A key factor is termed the intrinsic ability of the metabolising systems in the organ to biotransform the drug. This partly depends on the structure and physicochemical characteristics of the agent and often how closely it resembles an endogenous chemical. This ‘intrinsic clearance’ is independent of other key factors such as blood flow and protein binding. Indeed, those two latter factors, together with its other physicochemical properties, all influence how much drug is actually presented to the biotransforming enzymes in any given timeframe. Clearly, if a drug is very tightly protein bound, it might be confined in the plasma or deep tissues. Similarly, an extremely lipophilic agent might be trapped in membranes or fatty tissues. These factors will retard the availability and presentation of free drug to the enzyme systems.
1.3.5 Clearance: influencing factors
If we can measure and account for all these factors, perhaps physically and/or theoretically, we can estimate whether a drug is relatively easy or difficult to clear. Usually, because the liver is the largest biotransforming organ and makes the greatest contribution to the clearance of most drugs, it is the main focus of attempts to categorize the degree of efficiency of biotransformation. Although much of pharmacokinetic analyses focus on the liver, terms such as extraction and intrinsic clearance can also be applied to other organs with significant biotransforming capability. So, for any given biotransforming organ, drug clearance is influenced by organ size and blood flow, the total amount of biotransforming enzymes, their intrinsic clearance, protein binding, and lipophilicity. Total body clearance, as mentioned in section 1.3.1, is the removal of drug from all tissues and is the sum total of all the individual ‘clearances’ of a drug, ranging from the cellular to the organ level.
1.4 First pass and drug extraction
1.4.1 First pass: gut contribution
From a therapeutic perspective, the primary goal is to use the most practical, robust, and painless method of administering a drug regularly, so that its plasma concentrations can reach the therapeutic window and hopefully stay there. Whilst oral dosage is the obvious choice here, this is rather like attempting to enter a well‐garrisoned castle by politely knocking at the front gate. Indeed, in many cases (Figure 1.3), even assuming oral absorption is complete, relatively little of the drug actually enters the circulation after what is termed first pass, which is the result of the biotransformational processes that essentially destroy most of the pharmacological impact of many drugs, by clearing them to metabolites.
Figure 1.3 The first pass of an orally dosed highly cleared drug showing the removal of drug by the gut and liver, leading to relatively low levels of the drug actually reaching the circulation
However, the first‐pass process seems to start quite promisingly, as most drugs easily diffuse through the membranes of the gut enterocytes passively, due to their relative lipophilicity or if they are more water soluble, they can enter through the spaces between the tight junctions of the enterocytes, which is known as the paracellular pathway. Indeed, water‐soluble drugs can even be assisted by transporter systems called solute carriers (Chapter 2.6.3). These transporters normally convey vital nutrients such as amino acids as well as drugs with similar physicochemical characteristics (like some statins).
Once the drug penetrates the enterocytes, the situation changes dramatically. Until relatively recently, it was not fully understood just how great a contribution the gut biotransforming systems made to first pass. This process begins with the efflux proteins (Chapter 4.4.7), which will expel many drugs back into the gut lumen. It is thought that drug molecules can be reabsorbed and expelled repeatedly, which can retard absorption, and/or provide more opportunity for the agent to meet the biotransforming enzymes; it may even be part of a cooperative process that prevents saturation of these enzymes. Although this might occur for endogenous substrates, it is more difficult to establish with drugs1.
It is now clear that enterocytes contain many of the most significant hepatically expressed biotransforming enzymes and they exert an impact in terms of drug metabolism which far exceeds their actual mass; this suggests that biotransformation in the gut must be exceptionally efficient. This is probably because of a combination of high local drug concentrations, high intrinsic clearance, and long gut transit times. Indeed, limiting factors, such as restricted blood flow and protein binding, are absent also. It is well established that about a third of drugs used commonly undergo significant gut metabolism and with some agents like the benzodiazepine midazolam and the immunosuppressive agent cyclosporine, up to half the dose can be biotransformed through this route before the drug even reaches the liver2.
1.4.2 First pass: hepatic contribution
Whilst first pass is clearly an integrated enterprise between the gut and the liver, determining the respective contributions of the two organ systems to this enterprise is difficult. It could be desirable to achieve this during clinical research with existing drugs, or perhaps during the development of a new drug, when it is necessary to know where metabolism occurs in order to anticipate future drug–drug interactions, for example. In the past, isolating the contribution of the gut has been accomplished in patients by sampling directly from the hepatic portal system3, or less invasively, through the use of inhibitors that inactivated gut metabolising capability, allowing an estimate of hepatic metabolism4. More recently, sophisticated pharmacokinetic models have been developed that use various estimated parameters to calculate hepatic metabolism without recourse to such problematic methods5, and this is a key area in experimental drug development, which will be discussed in more detail in Appendix A.
At a fairly basic level, the liver’s contribution to first pass is usually stated as hepatic extraction, which is the difference between the drug level in portal blood that enters the liver (100%) and the amount that escapes intact and unmetabolized (that is, 100% minus the metabolized fraction) after a single pass through the organ. Extraction is usually termed E and is defined as the extraction ratio, or
Clinically, most drugs’ hepatic extraction ratios will either be high (E > 0.7) or low (E < 0.3), with a few agents falling into the intermediate category (E is 0.3–0.7). For high‐extraction drugs, the particular enzyme system that metabolizes this drug may be present in large amounts and drug processing is very rapid. As already mentioned, a close structural resemblance to an endogenous agent, which is normally processed in great quantity on a daily basis, will probably lead to high extraction. Hence, the early anti‐HIV drug AZT (zidovudine), is a close structural analogue of the DNA constituent thymidine and so possesses a half‐life of an hour or less in humans. In the case of a high‐extraction drug, intrinsic clearance is so high that the only limitation in the liver’s ability to metabolize this type of drug is its rate of arrival, which is governed by blood flow.
So, in the case of a high‐clearance drug, where the liver’s intrinsic ability to clear it is very high:
So, basically, hepatic clearance is directly proportional to blood flow:
Theoretically, hepatic and intrinsic clearance would be the same value if blood flow was infinite. In the real world, there are, of course, many other factors that influence clearance, and in the early 1970s, it was realised that some form of theoretical model needed to be evolved that would guide the process of predicting hepatic clearance and that took these other factors into account, such as protein binding and intrinsic clearance, as well as blood flow. This was the ‘well stirred model’ of hepatic clearance and can be summarized thus:
where Clh is hepatic clearance, fu is the fraction of unbound drug, Q is liver blood flow, and Clint is hepatic intrinsic clearance.
This equation makes many assumptions, but an important one is that it concerns the clearance of drug from whole blood, rather than plasma5. So to employ this model, we can use data from in vitro methods, such as derived from human cells or tissues to calculate an intrinsic clearance. Protein binding can also be measured in the laboratory and during patient studies. Current ultrasound techniques allow for accurate and noninvasive real‐time determination of liver blood flow6. Of course, during intensive exercise, values can fall temporarily by more than 70%, but during normal day‐to‐day living, blood flow through the liver does not change very much. So we can combine all this information in our well‐stirred model to estimate the clearance of a high‐extraction drug in a typical healthy 70 kg adult.
However, as we reach old age, hepatic blood flow can fall to approaching half what it was in our twenties (Chapter 7.3.1). In addition, liver damage from end‐stage cirrhotic alcoholism (Chapter 7.7.6), or any long‐term impairment in cardiac output, will also reduce liver blood flow. All these circumstances have been shown to retard the clearance of high‐extraction drugs clinically and should be borne in mind during drug dosage determination in these patients.
Many drugs are bound in plasma to proteins such as human serum albumin (HSA) or alpha‐1 acid glycoprotein (AGP). HSA usually transports endogenous acidic agents, such as fatty acids, bilirubin, and bile acids, although it also binds drugs such as warfarin, ibuprofen, and diazepam. AGP, which is also known as orosomucoid, is one of a number of acute phase proteins, which can increase several‐fold in plasma in response to infections or increased inflammatory status and is regulated by cytokines. Elevated AGP levels can last for weeks or months and have been linked with life‐threatening conditions such as stroke7,8. AGP will bind many basic drugs such as erythromycin, some antimalarials, and protease inhibitors; indeed, changes in AGP during infections have long been known to strongly impact drug plasma disposition9,10.
Usually, for any given drug, there is equilibrium between protein‐bound and free drug. In effect, high‐extraction drugs are cleared so avidly that the free drug disappears into the metabolizing system and the bound pool of drug eventually becomes exhausted. As the protein binding of a high‐extraction drug is no barrier to its removal by the liver, these drugs are sometimes described as undergoing unrestricted clearance. Drugs in this category include pethidine (known as meperidine or Demerol in the United States), metoprolol, propranolol, lignocaine, nifedipine, fentanyl and verapamil.
1.4.3 First pass: low‐extraction drugs
On the opposite end of the scale (E < 0.3), low‐extraction drugs are cleared slowly, as the metabolizing enzymes have some difficulty in oxidizing them, perhaps due to stability in the structure, or the low capacity and activity of the metabolizing enzymes. The metabolizing enzymes may also be present only in very low levels. These drugs are considered to be low intrinsic clearance drugs, as the inbuilt ability of the liver to remove them is relatively poor.
If a low‐extraction drug is not extensively bound to protein (less than 50% bound), then how much drug is cleared is related directly to the intrinsic clearance of that drug. In the case of a low‐extraction, strongly protein‐bound drug, then, clearance is hampered as the affinity of the liver for the drug is lower than that of the binding protein. The anticonvulsants phenytoin and valproate are both highly protein bound (∼ 90%) and low‐extraction drugs, so the amount of these drugs actually cleared by the liver really depends on how much unbound or free drug there is in the blood. This means that:
Therefore, clearance is proportional to the ability of the liver to metabolize the drug (Clintrinsic) as well as the amount of unbound or free drug in the plasma that is actually available for metabolism. Hepatic blood flow changes have little or no effect on low‐extraction drug plasma levels, but if the intrinsic ability of the liver to clear a low‐extraction drug falls even further (due to enzyme inhibition or gradual organ failure), there will be a significant increase in plasma and tissue free drug levels and dosage adjustment will be necessary. Conversely, if the intrinsic clearance increases (enzyme induction, Chapter 4.3) then free drug levels may fall and the therapeutic effects of the agent will be diminished.
It is worth noting that with drugs of low extraction and high protein binding, such as phenytoin and valproate, a reduction in total drug levels due to a fall in protein binding (perhaps due to renal problems or displacement by another, more tightly bound drug) will actually have no sustained effect on free drug plasma and tissue levels. This is because the ‘extra’ free drug will be cleared or enter the tissues and the bound/unbound drug ratio will quickly reassert itself. Since the free drug is pharmacologically active and potentially toxic whilst the bound drug is not, it is not usually necessary to increase the dose in these circumstances. The concentration of the free drug has the greatest bearing on dosage adjustment considerations. Laboratory assay systems are now routinely used to determine free drug levels with highly bound, low‐extraction drugs that are therapeutically monitored, such as with phenytoin and valproate. Other examples of low‐extraction drugs include paracetamol, mexiletine, diazepam, naproxen, and metronidazole. The term restrictive clearance is also used to describe these drugs, as their clearance is effectively restricted by their protein binding.
1.5 First pass and plasma drug levels
1.5.1 Introduction
As mentioned above, for many drugs, a significant amount of the oral dose is lost before it reaches the systemic circulation. To estimate a dosage regime that will place our plasma drug concentrations within our therapeutic window, we need to know how much drug is lost during the first pass process. To accomplish this, we can measure blood or plasma concentrations after the drug is given intravenously, where we can safely assume 100% absorption. Next, we measure drug concentrations after an oral dose, which will be significantly lower. Using pharmacokinetic methods and many blood measurements, we can determine the amount of drug measured in blood after intravenous or oral dosage. We know the dose, so we can calculate the amount of drug that survives the first pass. This is termed F or the absolute bioavailability of the drug. It can be defined as
As we have seen with clearance, F is not just one figure. It is the product of Fa (absorption into the enterocytes), Fg (amount that survives gut metabolism), and Fh (the amount that survives hepatic metabolism), assuming other organs do not contribute significantly.
