Human Drug Metabolism: An Introduction

Human Drug Metabolism: An Introduction, Second Edition......Page 2
Contents......Page 10
Preface......Page 14
Preface to First Edition......Page 16
1.1 Therapeutic window......Page 18
1.2 Consequences of drug concentration changes......Page 20
1.3 Clearance......Page 22
1.4 Hepatic extraction and intrinsic clearance......Page 24
1.5 First pass and plasma drug levels......Page 26
1.6 Drug and xenobiotic metabolism......Page 28
2.2 Threat of lipophilic hydrocarbons......Page 30
2.3 Cell communication......Page 31
2.4 Potential food toxins......Page 33
2.6 Biotransformation and xenobiotic cell entry......Page 35
3.2 Capture of lipophilic molecules......Page 40
3.3 Cytochrome P450s: classification and basic structure......Page 42
3.4 CYPs – main and associated structures......Page 44
3.5 Human CYP families and their regulation......Page 50
3.6 Main human CYP families......Page 52
3.7 Cytochrome P450 catalytic cycle......Page 60
3.8 Flavin Monooxygenases (FMOs)......Page 64
3.9 How CYP isoforms operate in vivo......Page 67
3.10 Aromatic ring hydroxylation......Page 70
3.11 Alkyl oxidations......Page 71
3.12 ‘Rearrangement’ reactions......Page 75
3.13 Other oxidation processes......Page 80
3.14 Control of CYP metabolic function......Page 81
4.1 Introduction......Page 82
4.2 Causes of accelerated clearance......Page 85
4.3 Enzyme induction......Page 86
4.4 Mechanisms of enzyme induction......Page 88
4.5 Induction – general clinical aspects......Page 103
5.1 Introduction......Page 110
5.2 Inhibition of metabolism – general aspects......Page 112
5.3 Mechanisms of inhibition......Page 113
5.4 Cell transport systems and inhibition......Page 128
5.5 Major clinical consequences of inhibition of drug clearance......Page 131
5.6 Use of inhibitors for positive clinical intervention......Page 136
5.7 Summary......Page 140
6.1 Introduction......Page 142
6.2 Glucuronidation......Page 143
6.3 Sulphonation......Page 155
6.4 The GSH system......Page 158
6.5 Glutathione S-transferases......Page 161
6.6 Epoxide hydrolases......Page 166
6.7 Acetylation......Page 168
6.9 Esterases/amidases......Page 169
6.11 Phase III transport processes......Page 170
6.12 Biotransformation-integration of processes......Page 173
7.2 Genetic polymorphisms......Page 176
7.3 Effects of age on drug metabolism......Page 209
7.4 Effects of diet on drug metabolism......Page 213
7.5 Gender effects......Page 217
7.6 Smoking......Page 218
7.7 Effects of ethanol on drug metabolism......Page 219
7.9 Effects of disease on drug metabolism......Page 227
7.10 Summary......Page 229
8.2 Reversible drug adverse effects: Type A......Page 230
8.3 Irreversible drug toxicity: Type B......Page 237
8.4 Type B1 necrotic reactions......Page 241
8.5 Type B2 reactions: immunotoxicity......Page 253
8.6 Type B3 reactions: role of metabolism in cancer......Page 268
8.7 Summary of biotransformational toxicity......Page 283
A.1 Introduction......Page 286
A.2 Analytical techniques......Page 288
A.3 Human liver microsomes......Page 289
A.4 Human hepatocytes......Page 290
A.5 Human cell lines......Page 292
A.7 Animal model developments in drug metabolism......Page 293
A.8 Toxicological metabolism-based assays......Page 295
A.9 In silico studies......Page 298
A.10 Summary......Page 299
B.2 Opiates......Page 302
B.3 Cocaine......Page 309
B.4 Hallucinogens......Page 311
B.5 Amphetamines......Page 315
B.6 Cannabis......Page 321
B.7 Dissociative anaesthetics......Page 324
C.2 A first-class answer......Page 328
C.3 Preparation......Page 329
C.4 The day of reckoning......Page 331
Appendix D: Summary of Major CYP Isoforms and their Substrates, Inhibitors and Inducers......Page 334
Suggested Further Reading......Page 336
Index......Page 346