Human Drug Metabolism

Preface 1 Introduction 1.1 Therapeutic window 1.1.1 Introduction 1.1.2 Therapeutic index 1.1.3 Changes in dosage 1.1.4 Changes in rate of removal 1.2 Consequences of drug concentration changes 1.2.1 Drug failure 1.2.2 Drug toxicity 1.3 Clearance 1.3.1 Definitions 1.3.2 Clearance and elimination 1.3.3 Biotransformation prior to elimination 1.3.4 Intrinsic clearance 1.3.5 Clearance: influencing factors 1.4 First Pass and Drug Extraction 1.4.1 First Pass-gut contribution 1.4.2 First Pass-hepatic contribution 1.4.3 First pass-low extraction drugs 1.5 First pass and plasma drug levels 1.5.1. Introduction 1.5.2 Changes in clearance and plasma 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 2.3.1 Signal molecule evolution 2.3.2 Lipophilic hydrocarbons as signal molecules 2.4 False signal molecules: bioprotection 2.4.1 Endocrine disruption 2.4.2 Endocrine disruption: problems and solutions 2.4.3 Endocrine disruption: cosmetic and nutraceutical aspects 2.4.4 Endocrine disruption: microRNAs 2.5 Sites of biotransforming enzymes 2.6 Biotransformation and xenobiotic cell entry 2.6.1 Role of the liver 2.6.2 Drug and xenobiotic uptake: transporter systems 2.6.3 Hepatic and gut uptake (influx) transporter systems 2.6.4 Aims of biotransformation 2.6.5 Task of biotransformation 2.6.6 Phase's I-III of biotransformation-descriptions & classifications 2.6.7 Biotransformation and drug action References 3 How Oxidative Systems Metabolize Substrates 3.1 Introduction 3.2 Capture of lipophilic molecules 3.3 Cytochrome P450s: nomenclature and methods of study 3.3.1 Classification 3.3.2 Methods of Analysis 3.3.3. CYP key features and capabilities 3.4 CYPs - main and associated structures 3.4.1 General structure 3.4.2 Haem moiety 3.4.3 CYP flexible regions 3.4.4 Substrate binding in CYPs 3.4.5 Homotropic binding in CYPs 3.4.6 Heterotropic binding in CYPs 3.4.7. CYP Complex formation. 3.4.8 CYP REDOX partners (i) P 450 oxidoreductase (POR) 3.4.9. CYP REDOX partners (ii) Cytochromeb5 3.5 Human CYP families and their regulation 3.5.1 CYP regulation-lifespan 3.5.2 CYP regulation-transcriptional 3.5.3 CYP Regulation: post-translational 3.6 Main human CYP families 3.6.1 CYP1A series 3.6.2 CYP 2 series 3.6.3 CYP 3A series 3.7 Cytochrome P450 catalytic cycle 3.7.1 Substrate binding 3.7.2 Oxygen binding 3.7.3 Oxygen scission (splitting) 3.7.4 Insertion of oxygen into substrate 3.7.5 Release of product 3.7.6 Reductions 3.8 Flavin Monooxygenases (FMO's) 3.8.1 Introduction 3.8.2 Structure 3.8.3 Mechanism of catalysis 3.8.4 Variation and expression 3.8.5 FMOs in drug development 3.9 How CYP isoforms operate in vivo 3.9.1 Illustrative use of structures 3.9.2 Primary purposes of CYPs 3.9.3 Role of oxidation 3.9.4 Summary of CYP operations 3.10 Aromatic ring hydroxylation 3.10.1 Nature of aromatics 3.10.2 The oxidation of benzene 3.11 Alkyl oxidations 3.11.1 Saturated alkyl groups 3.11.2 Unsaturated alkyl groups 3.11.3 Pathways of alkyl metabolism 3.12 'Rearrangement' reactions 3.12.1 Dealkylations 3.12.2 Deaminations 3.12.3 Dehalogenations 3.13 Other oxidation processes 3.13.1 Primary amine oxidations 3.13.2 Oxidation of alcohol and aldehydes 3.13.3 Monoamine oxidase (MAO) 3.14 Control of CYP metabolic function References 4 Induction of Cytochrome P 450 Systems 4.1 Introduction 4.1.1 How living systems self-regulate-overview 4.1.2 Self-regulation in drug metabolism 4.1.3 Self-regulatory responses to drugs-summary 4.2 Causes of accelerated clearance 4.3 Enzyme induction 4.3.1 Types of inducer 4.3.2 . Common Features of Inducers and Clinical Significance 4.4 Mechanisms of enzyme induction 4.4.1 Introduction 4.4.2 CYPs 1A1/1A2 and 1B1 induction 4.4.3 CYP 2B6 2C8/2C9/C19 and 3A4 Induction 4.4.4 CYP 2E1 induction 4.4.5 CYP2D6 4.4.6 Reversal of induction 4.4.7 Cell transport systems and induction: P-glycoprotein 4.4.8 Induction Processes: summary 4.5 Induction - general clinical aspects 4.5.1 Introduction 4.5.2 Anti -epileptic agents 4.5.3 OTC (over the counter) and online herbal preparations 4.5.4 Anticoagulant drugs 4.5.5 Oral contraceptives/steroids 4.5.6 Antiviral/antibiotic drugs 4.5.7 Anti-cancer drugs 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 5.3.1 Introduction 5.3.2 Competitive inhibition 5.3.3 Non -competitive inhibition 5.3.4 Uncompetitive inhibition 5.4 Mechanisms of irreversible inhibition 5.4.1. Introduction 5.4.2. Mechanism-based quasi-irreversible inhibitors 5.4.3. Mechanism-based irreversible inhibitors 5.5. Clinical Consequences of irreversible inhibition 5.5.1. Introduction 5.5.2 Quasi-irreversible inhibitors; the SSRI's 5.5.3 Mechanism- based inhibitors: grapefruit juice 5.5.4 Mechanism- based inhibitors: other juice products 5.5.5 OTC herbal remedy inhibitors 5.6 Cell transport systems and inhibition 5.6.1 Uptake (Influx) transporters: OATPs 5.6.2 Efflux transporters: P-glycoprotein (P-gp) 5.7 Major clinical consequences of inhibition of drug clearance 5.7.1 Introduction 5.7.2 Torsades des pointes (TdP) 5.7.3 Sedative effects 5.7.4 Muscle damage (rhabdomyolysis) 5.7.5 Excessive hypotension 5.7.6 Ergotism 5.7.7 Excessive anticoagulation 5.8 Use of inhibitors for positive clinical intervention 5.8.1 Introduction 5.8.2 CYP inhibitors and female hormone- dependent tumours 5.8.3 CYP inhibitors and male hormone- dependent tumours 5.8.4 CYP inhibitors and manipulation of prescription drug disposition 5.8.5 The use of inhibitors to increase drug efficacy 5.8.6 The use of inhibitors to reduce toxic metabolite formation 5.8.7 The use of inhibitors to reduce drug costs 5.8.8. Use of inhibition in alcoholism 5.9 Summary References 6 Conjugation and Transport Processes 6.1 Introduction 6.2 Glucuronidation 6.2.1 UGTs 6.2.2 UGT mode of operation 6.2.3 UGT isoforms 6.2.4 UGTs and bilirubin 6.2.5 UGTs and bile acids 6.2.6 Role of glucuronidation in drug clearance 6.2.7 Types of glucuronides formed 6.2.8 Control of UGTs 6.2.9 Induction of UGTs-clinical consequences 6.2.10 UGT inhibition-bilirubin metabolism 6.2.11 UGT inhibition-drug clearance 6.2.12 The microbiome and drug metabolism-passengers or crew? 6.3 Sulphonation 6.3.1 Introduction 6.3.2 SULT structure related to catalytic operation 6.3.3 Control of SULT enzymes 6.3.4 SULTs and cancer 6.4 The GSH system 6.4.1 Introduction 6.4.2 GSH system maintenance 6.5 Glutathione-S-transferases 6.5.1 Structure and location 6.5.2 Mode of operation 6.5.3 GST classes 6.5.4 Control of GSTs: overview 6.5.5 Control of GSTs and reactive species 6.5.6 Control of GSTs:the nrf2 system. 6.6 Epoxide hydrolases 6.6.1 Nature of Epoxides 6.6.2 Epoxide hydrolases 6.6.3 Epoxide hydrolases; structure, mechanisms of action and regulation 6.7 Acetylation 6.8 Methylation 6.9 Esterases/amidases 6.10 Amino acid conjugation (mainly glycine) 6.11 Phase III transport processes 6.11.1 Introduction 6.11.2 ABC Efflux transporters 6.11.3 RLIP76 6.12 Biotransformation- integration of processes References 7 Factors Affecting Drug Metabolism 7.1 Introduction 7.2 Genetic polymorphisms 7.2.1 Introduction 7.2.2 Clinical implications 7.2.3 Genetic polymorphisms in CYP systems 7.2.4 Genetic polymorphisms in non-conjugative systems 7.2.5 Conjugative polymorphisms: acetylation 7.2.6 Conjugative polymorphisms: methylation 7.2.7 Conjugative polymorphisms: UGT 1A1 7.2.8 Conjugative polymorphisms: sulphonation 7.2.9 Other Conjugative polymorphisms-Glutathione-S-transferases 7.2.10 Transporter polymorphisms 7.2.11 Polymorphism detection: clinical and practical issues 7.3 Effects of age on drug metabolism 7.3.1 The elderly 7.3.2 Drug Clearance in Neonates and children 7.4 Effects of diet on drug metabolism 7.4.1 Polyphenols 7.4.2 Barbecued meat 7.4.3 Cruciferous vegetables 7.4.4 Other vegetable effects on metabolism 7.4.5 Caffeine 7.4.6 Diet - general effects 7.5 Gender effects 7.6 Smoking 7.7 Effects of ethanol on drug metabolism 7.7.1 Context of ethanol usage 7.7.2 Ethanol metabolism 7.7.3 Ethanol and inhibitors of ALDH 7.7.4 Mild ethanol usage and drug clearance 7.7.5 Heavy ethanol usage and paracetamol 7.7.6 Alcoholic liver disease 7.7.7 Effects of cirrhosis on drug clearance 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 8.2.1 Intensification of pharmacologic effect: Type A1 8.2.2 Off-target reversible effects: methaemoglobin formation: Type A2 8.2.3 Predictable overdose toxicity: Type A3 8.3 Unpredictable drug adverse effects: Type B 8.3.1 Idiosyncratic and overdose toxicity: similarities and differences 8.3.2 Type B1 necrosis: Troglitazone 8.3.3 Type B1 necrosis: Trovafloxacin 8.3.4 Type B2 reactions: immunotoxicity 8.4. Nature of drug-mediated immune responses 8.4.1 Anaphylaxis 8.4.2. DRESS/Anticonvulsant hypersensitivity syndrome (AHS) 8.4.3. Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 8.4.4. Blood Dyscrasias 8.4.5. Prediction of Idiosyncratic reactions 8.5 Type B3 reactions: role of metabolism in cancer 8.5.1 Sources of risks of malignancy 8.5.2 Risks of malignancy and drug development 8.5.3 Environmental carcinogenicity risks 8.5.4 Occupational carcinogens 8.5.5 Dietary carcinogens-acrylamide 8.5.6 Dietary carcinogens-aflatoxins 8.6 Summary of biotransformational toxicity References Appendix A Drug 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.4.1 Analytical techniques A.4.2 Human liver microsomes A.4.3. Heterologous recombinant systems A.4.4. Liver Slices A.4.5. Human hepatocytes A.5 Animal model developments in drug metabolism A.5.1 Introduction A.5.2 Genetic modification of animal models A.5.3 'Humanized' mice A.6 Toxicological assays A.6.1. Aims A.6.2 Cell viability assays A.6.3 'One Compartment' Cell Models A.6.4. 'Two Compartment Models' A.6.5. DNA and Chromosomal toxicity assays A.6.6. the Ames Test A.6.7. Comet Assay A.6.8. Micronucleus Test A.6.9. Toxicology in drug discovery A.7 In silico approaches A.8. Summary References Appendix B Metabolism 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! References Appendix C Examination 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 Summary of Major CYP Isoforms and their Substrates, Inhibitors and Inducers Index