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電子書籍詳細


洋書 kinoppy

ヒトの薬物代謝(第3版)

Human Drug Metabolism

3

Coleman, Michael D.

Wiley-Blackwell 2019/12
688p.
出版国: US
ISBN: 9781119458562
eISBN: 9781119458616
KNPID: EY00372387
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Full Description

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.

Table of Contents

Preface xv

1 Introduction 1

1.1 Therapeutic window 1

1.1.1 Introduction 1

1.1.2 Therapeutic index 3

1.1.3 Changes in dosage 3

1.1.4 Changes in rate of removal 4

1.2 Consequences of drug concentration changes 4

1.2.1 Drug failure 4

1.2.2 Drug toxicity 5

1.3 Clearance 6

1.3.1 Definitions 6

1.3.2 Clearance and elimination 7

1.3.3 Biotransformation prior to elimination 7

1.3.4 Intrinsic clearance 8

1.3.5 Clearance: influencing factors 8

1.4 First pass and drug extraction 9

1.4.1 First pass: gut contribution 9

1.4.2 First pass: hepatic contribution 10

1.4.3 First pass: low‐extraction drugs 12

1.5 First pass and plasma drug levels 13

1.5.1 Introduction 13

1.5.2 Changes in clearance and plasma levels 14

1.6 Drug and xenobiotic metabolism 14

References 15

2 Drug Biotransformational Systems – Origins and Aims 17

2.1 Biotransforming enzymes 17

2.2 Threat of lipophilic hydrocarbons 18

2.3 Cell communication 19

2.3.1 Signal molecule evolution 19

2.3.2 Lipophilic hydrocarbons as signal molecules 20

2.4 False signal molecules: bioprotection 22

2.4.1 Endocrine disruption 22

2.4.2 Endocrine disruption: problems and solutions 23

2.4.3 Endocrine disruption: cosmetic and nutraceutical aspects 24

2.4.4 Endocrine disruption: microRNAs 25

2.5 Sites of biotransforming enzymes 26

2.6 Biotransformation and xenobiotic cell entry 27

2.6.1 Role of the liver 27

2.6.2 Drug and xenobiotic uptake: transporter systems 29

2.6.3 Hepatic and gut uptake (influx) transporter systems 30

2.6.4 Aims of biotransformation 31

2.6.5 Task of biotransformation 32

2.6.6 Phase’s I–III of biotransformation: descriptions and classifications 33

2.6.7 Biotransformation and drug action 34

References 34

3 How Oxidative Systems Metabolise Substrates 37

3.1 Introduction 37

3.2 Capture of lipophilic molecules 37

3.3 Cytochrome P450s: nomenclature and methods of study 38

3.3.1 Classification 38

3.3.2 Methods of analysis 40

3.3.3 CYP key features and capabilities 42

3.4 CYPs: main and associated structures 44

3.4.1 General structure 44

3.4.2 Haem moiety 44

3.4.3 CYP flexible regions 45

3.4.4 Substrate binding in CYPs 46

3.4.5 Homotropic binding in CYPs 47

3.4.6 Heterotropic binding in CYPs 49

3.4.7 CYP complex formation 50

3.4.8 CYP REDOX partners (i): P450 oxidoreductase (POR) 50

3.4.9 CYP REDOX partners (ii): Cytochrome b5 52

3.5 Human CYP families and their regulation 54

3.5.1 CYP regulation: lifespan 55

3.5.2 CYP regulation: transcriptional 56

3.5.3 CYP regulation: post‐translational 58

3.6 Main human CYP families 59

3.6.1 CYP1A series 59

3.6.2 CYP2 series 61

3.6.3 CYP3A series 69

3.7 Cytochrome P450 catalytic cycle 71

3.7.1 Substrate binding 72

3.7.2 Oxygen binding 72

3.7.3 Oxygen scission (splitting) 74

3.7.4 Insertion of oxygen into substrate 75

3.7.5 Release of product 75

3.7.6 Reductions 76

3.8 Flavin monooxygenases (FMOs) 76

3.8.1 Introduction 76

3.8.2 Structure 77

3.8.3 Mechanism of catalysis 78

3.8.4 Variation and expression 80

3.8.5 FMOs in drug development 80

3.9 How CYP isoforms operate in vivo 81

3.9.1 Illustrative use of structures 82

3.9.2 Primary purposes of CYPs 82

3.9.3 Role of oxidation 83

3.9.4 Summary of CYP operations 84

3.10 Aromatic ring hydroxylation 84

3.10.1 Nature of aromatics 84

3.10.2 Oxidation of benzene 85

3.11 Alkyl oxidations 86

3.11.1 Saturated alkyl groups 86

3.11.2 Unsaturated alkyl groups 87

3.11.3 Pathways of alkyl metabolism 89

3.12 Rearrangement reactions 90

3.12.1 Dealkylations 90

3.12.2 Deaminations 93

3.12.3 Dehalogenations 94

3.13 Other oxidation processes 94

3.13.1 Primary amine oxidations 94

3.13.2 Oxidation of alcohol and aldehydes 96

3.13.3 Monoamine oxidase (MAO) 96

3.14 Control of CYP metabolic function 97

References 97

4 Induction of Cytochrome P450 Systems 109

4.1 Introduction 109

4.1.1 How living systems self‐regulate: overview 109

4.1.2 Self‐regulation in drug metabolism 112

4.1.3 Self‐regulatory responses to drugs: summary 117

4.2 Causes of accelerated clearance 117

4.3 Enzyme induction 118

4.3.1 Types of inducers 118

4.3.2 Common features of inducers and clinical significance 120

4.4 Mechanisms of enzyme induction 121

4.4.1 Introduction 121

4.4.2 CYPs 1A1/1A2 and 1B1 induction 122

4.4.3 CYP 2B6 2C8/2C9/C19 and 3A4 induction 126

4.4.4 CYP 2E1 induction 138

4.4.5 CYP2D6 140

4.4.6 Reversal of induction 141

4.4.7 Cell transport systems and induction: P‐glycoprotein 143

4.4.8 Induction processes: summary 148

4.5 Induction: general clinical aspects 149

4.5.1 Introduction 149

4.5.2 Anti‐epileptic agents 150

4.5.3 OTC (over the counter) and online herbal preparations 155

4.5.4 Anticoagulant drugs 158

4.5.5 Oral contraceptives/steroids 160

4.5.6 Antiviral/antibiotic drugs 161

4.5.7 Anticancer drugs 163

4.6 Induction: practical considerations 165

4.7 Induction vs. inhibition: which ‘wins’? 165

4.8 Induction: long‐term impact 166

References 167

5 Cytochrome P450 Inhibition 183

5.1 Introduction 183

5.2 Inhibition of metabolism: general aspects 186

5.3 Mechanisms of reversible inhibition 187

5.3.1 Introduction 187

5.3.2 Competitive inhibition 188

5.3.3 Noncompetitive inhibition 195

5.3.4 Uncompetitive inhibition 196

5.4 Mechanisms of irreversible inhibition 196

5.4.1 Introduction 196

5.4.2 Mechanism‐based quasi‐irreversible inhibitors 198

5.4.3 Mechanism‐based irreversible inhibitors 198

5.5 Clinical consequences of irreversible inhibition 200

5.5.1 Introduction 200

5.5.2 Quasi‐irreversible inhibitors: the SSRIs 201

5.5.3 Mechanism‐based inhibitors: grapefruit juice 213

5.5.4 Mechanism‐based inhibitors: other juice products 216

5.5.5 OTC herbal remedy inhibitors 218

5.6 Cell transport systems and inhibition 220

5.6.1 Uptake (Influx) transporters: OATPs 220

5.6.2 Efflux transporters: P‐glycoprotein (P‐gp) 222

5.7 Major clinical consequences of inhibition of drug clearance 226

5.7.1 Introduction 226

5.7.2 Torsades de pointes (TdP) 227

5.7.3 Sedative effects 232

5.7.4 Muscle damage (rhabdomyolysis) 233

5.7.5 Excessive hypotension 234

5.7.6 Ergotism 235

5.7.7 Excessive anticoagulation 235

5.8 Use of inhibitors for positive clinical intervention 236

5.8.1 Introduction 236

5.8.2 CYP inhibitors and female hormone‐dependent tumours 237

5.8.3 CYP inhibitors and male hormone‐dependent tumours 238

5.8.4 CYP inhibitors and manipulation of prescription drug disposition 239

5.8.5 Use of inhibitors to increase drug efficacy 241

5.8.6 Use of inhibitors to reduce toxic metabolite formation 242

5.8.7 Use of inhibitors to reduce drug costs 245

5.8.8 Use of inhibition in alcoholism 246

5.9 Summary 246

References 246

6 Conjugation and Transport Processes 263

6.1 Introduction 263

6.2 Glucuronidation 265

6.2.1 UGTs 265

6.2.2 UGT mode of operation 266

6.2.3 UGT isoforms 268

6.2.4 UGTs and bilirubin 271

6.2.5 UGTs and bile acids 272

6.2.6 Role of glucuronidation in drug clearance 273

6.2.7 Types of glucuronides formed 274

6.2.8 Control of UGTs 276

6.2.9 Induction of UGTs: clinical consequences 278

6.2.10 UGT inhibition: bilirubin metabolism 280

6.2.11 UGT inhibition: drug clearance 281

6.2.12 Microbiome and drug metabolism: passengers or crew? 282

6.3 Sulphonation 285

6.3.1 Introduction 285

6.3.2 SULT structure related to catalytic operation 287

6.3.3 Control of SULT enzymes 289

6.3.4 SULTs and cancer 289

6.4 The GSH system 290

6.4.1 Introduction 290

6.4.2 GSH system maintenance 292

6.5 Glutathione S‐transferases 293

6.5.1 Structure and location 293

6.5.2 Mode of operation 295

6.5.3 GST classes 296

6.5.4 Control of GSTs: overview 300

6.5.5 Control of GSTs and reactive species 301

6.5.6 Control of GSTs: the nrf2 system 302

6.6 Epoxide hydrolases 304

6.6.1 Nature of epoxides 304

6.6.2 Epoxide hydrolases 304

6.6.3 Epoxide hydrolases: structure, mechanisms of action, and regulation 306

6.7 Acetylation 307

6.8 Methylation 309

6.9 Esterases/amidases 311

6.10 Amino acid conjugation (mainly glycine) 314

6.11 Phase III transport processes 315

6.11.1 Introduction 315

6.11.2 ABC Efflux transporters 315

6.11.3 RLIP76 320

6.12 Biotransformation: integration of processes 320

References 322

7 Factors Affecting Drug Metabolism 331

7.1 Introduction 331

7.2 Genetic polymorphisms 332

7.2.1 Introduction 332

7.2.2 Clinical implications 336

7.2.3 Genetic polymorphisms in CYP systems 341

7.2.4 Genetic polymorphisms in nonconjugative systems 369

7.2.5 Conjugative polymorphisms: acetylation 374

7.2.6 Conjugative polymorphisms: methylation 381

7.2.7 Conjugative polymorphisms: UGT 1A1 385

7.2.8 Conjugative polymorphisms: sulphonation 388

7.2.9 Other conjugative polymorphisms: Glutathione S‐transferases 389

7.2.10 Transporter polymorphisms 390

7.2.11 Polymorphism detection: clinical and practical issues 392

7.3 Effects of age on drug metabolism 395

7.3.1 The elderly 395

7.3.2 Drug clearance in neonates and children 398

7.4 Effects of diet on drug metabolism 401

7.4.1 Polyphenols 401

7.4.2 Barbecued meat 402

7.4.3 Cruciferous vegetables 403

7.4.4 Other vegetable effects on metabolism 404

7.4.5 Caffeine 404

7.4.6 Diet: general effects 405

7.5 Gender effects 406

7.6 Smoking 409

7.7 Effects of ethanol on drug metabolism 412

7.7.1 Context of ethanol usage 412

7.7.2 Ethanol metabolism 413

7.7.3 Ethanol and inhibitors of ALDH 414

7.7.4 Mild ethanol usage and drug clearance 414

7.7.5 Heavy ethanol usage and paracetamol 415

7.7.6 Alcoholic liver disease 416

7.7.7 Effects of cirrhosis on drug clearance 420

7.8 Artificial livers 422

7.9 Effects of disease on drug metabolism 424

7.10 Summary 425

References 426

8 Role of Metabolism in Drug Toxicity 447

8.1 Adverse drug reactions: definitions 447

8.2 Predictable drug adverse effects: type A 448

8.2.1 Intensification of pharmacologic effect: type A1 448

8.2.2 Off‐target reversible effects and methaemoglobin formation: type A2 449

8.2.3 Predictable overdose toxicity: type A3 455

8.3 Unpredictable drug adverse effects: type B 470

8.3.1 Idiosyncratic and overdose toxicity: similarities and differences 470

8.3.2 Type B1 necrosis: troglitazone 471

8.3.3 Type B1 necrosis: trovafloxacin 473

8.3.4 Type B2 reactions: immunotoxicity 476

8.4 Nature of drug‐mediated immune responses 489

8.4.1 Anaphylaxis 489

8.4.2 DRESS/Anticonvulsant hypersensitivity syndrome (AHS) 491

8.4.3 Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 492

8.4.4 Blood dyscrasias 494

8.4.5 Prediction of idiosyncratic reactions 499

8.5 Type B3 reactions: role of metabolism in cancer 500

8.5.1 Sources of risks of malignancy 500

8.5.2 Risks of malignancy and drug development 501

8.5.3 Environmental carcinogenicity risks 502

8.5.4 Occupational carcinogens 503

8.5.5 Dietary carcinogens: acrylamide 513

8.5.6 Dietary carcinogens: aflatoxins 516

8.6 Summary of biotransformational toxicity 520

References 521

Appendix A Drug Metabolism in Drug Discovery 531

A.1 The pharmaceutical industry 531

A.2 Drug design and biotransformation: strategies 533

A.3 Animal and human experimental models: strategies 537

A.4 In vitro metabolism platforms and methods 539

A.4.1 Analytical techniques 539

A.4.2 Human liver microsomes 541

A.4.3 Heterologous recombinant systems 542

A.4.4 Liver slices 543

A.4.5 Human hepatocytes 543

A.5 Animal model developments in drug metabolism 550

A.5.1 Introduction 550

A.5.2 Genetic modification of animal models 551

A.5.3 ‘Humanized’ mice 552

A.6 Toxicological assays 553

A.6.1 Aims 553

A.6.2 Cell viability assays 554

A.6.3 ‘One compartment’ cell models 555

A.6.4 ‘Two compartment’ models 555

A.6.5 DNA and chromosomal toxicity assays 556

A.6.6 The Ames test 556

A.6.7 Comet assay 557

A.6.8 Micronucleus test 557

A.6.9 Toxicology in drug discovery 558

A.7 In silico approaches 561

A.8 Summary 564

References 565

Appendix B Metabolism of Major Illicit Drugs 571

B.1 Introduction 571

B.2 Opiates 572

B.3 Cocaine 582

B.4 Hallucinogens 585

B.5 Amphetamine derivatives 591

B.6 Cannabis 603

B.7 Dissociative anaesthetics 609

B.8 Charlie Don’t Surf! 616

References 617

Appendix C Examination Techniques 627

C.1 Introduction 627

C.2 A first‐class answer 627

C.3 Preparation 629

C.4 The day of reckoning 632

C.5 Foreign students 633

Appendix D Summary of Major CYP Isoforms and Their Substrates, Inhibitors, and Inducers 635

Index 639