Drug Disposition and Pharmacokinetics: Principles and Applications for Medicine, Toxicology and Biotechnology

Cover
Title Page
Copyright Page
Contents
Preface
Chapter 1 Setting the Scene: Concepts, Nature of Drugs, and Quality of Results
1.1 Introduction
1.2 Concepts and terminology: disposition and pharmacokinetics
1.3 Pharmacokinetic parameters
1.3.1 Half-life
1.3.2 Clearance and apparent volume of distribution
1.3.3 Area under the plasma concentration–time curve
1.3.4 Apparent oral clearance
1.4 Time–concentration–effect relationships
1.5 Properties of drugs and xenobiotics
1.6 Quality of the data
1.6.1 Quantification of analyte concentrations
1.6.2 Timing of samples
1.6.3 Quality control and method validation
1.7 References
Chapter 2 Drug Disposition and Fate
2.1 Introduction
2.2 Transport proteins
2.3 Absorption
2.3.1 Gastrointestinal tract
2.3.2 Drug transfer across the gastrointestinal tract
2.3.3 Other mucus membranes
2.3.4 Skeletal muscle
2.3.5 Skin
2.3.6 Absorption of macromolecules and nanoparticles
2.4 Distribution
2.4.1 Mechanisms of sequestration
2.4.2 Assessing the extent and location of distribution
2.4.3 Kinetics of distribution
2.5 Metabolism
2.5.1 Phase 1 metabolism
2.5.2 Phase 2 conjugations
2.5.3 Metabolism by microbiota
2.6 Excretion
2.6.1 Urine
2.6.2 Biliary excretion
2.6.3 Expired air
2.6.4 Saliva
2.6.5 Stomach and intestine
2.6.6 Breast milk
2.6.7 Other routes of excretion
2.6.8 Cycling processes
2.7 References
Chapter 3 Pharmacokinetic Modelling
3.1 Introduction
3.2 Fundamental concepts
3.2.1 Apparent volume of distribution
3.2.2 Clearance
3.3 Elimination
3.3.1 First-order elimination
3.3.2 Non-linear elimination
3.4 Intravenous infusions
3.4.1 Single-compartment model with first-order elimination
3.4.2 Two-compartment model with first-order elimination
3.5 First-order input and elimination
3.5.1 Absorption
3.5.2 Multiple dosing
3.6 Areas under the plasma concentration–time curve: trapezoidal method
3.7 Statistical moment theory
3.7.1 Estimating AUMC
3.8 Bioavailability and bioequivalence
3.8.1 Non-linear kinetics
3.8.2 Effect of systemic availability on plasma concentration–time curves
3.8.3 Factors affecting bioavailability
3.8.4 Bioequivalence
3.9 Physiological modelling
3.9.1 Practical considerations
3.10 Population kinetics
3.11 References
Chapter 4 Pharmacokinetics of Metabolism and Excretion
4.1 Introduction
4.2 Metabolite kinetics
4.2.1 Basic concepts
4.2.2 Fraction of metabolite formed
4.2.3 More complex situations
4.2.4 Effect of pre-systemic metabolism
4.2.5 Interconversion of drug and metabolite
4.2.6 Active metabolites and prodrugs
4.2.7 Kinetics of formed and preformed metabolites
4.3 Kinetics of urinary excretion
4.3.1 Renal clearance
4.3.2 Effect of urine flow rate
4.3.3 Estimating renal blood flow and glomerular filtration rate
4.3.4 Specific drug examples
4.4 Excretion in faeces
4.5 References
Chapter 5 Quantitative Pharmacological Relationships
5.1 Introduction
5.2 Concentration–effect relationships and dose–response curves
5.3 Concentration–effect relationships in vivo
5.4 Time-Dependent Models
5.4.1 Direct link and indirect link models
5.4.2 Temporal displacement
5.4.3 Inhomogeneity of plasma
5.4.4 Effects of unequal distribution in plasma
5.4.5 Pharmacokinetic distributional models
5.5 PK–PD modelling
5.5.1 PK–PD modelling under steady-state conditions
5.5.2 Use of effect-compartment models
5.5.3 Indirect-response models
5.5.4 Disease progression models
5.5.5 Time-related changes in pharmacodynamic parameters
5.5.6 Schedule dependence
5.5.7 Basic PK–PD versus system PK–PD
5.6 References
Chapter 6 Predictive Pharmacokinetics
6.1 Introduction
6.2 Physiochemical properties
6.2.1 Druggability
6.2.2 Drug-likeness
6.2.3 Dissolution studies
6.3 Metabolic stability
6.3.1 Microsomal intrinsic clearance
6.3.2 Hepatocytes
6.3.3 Recombinant human cytochromes
6.4 Plasma protein and tissue binding and blood/plasma ratios
6.4.1 Plasma protein binding
6.4.2 Erythrocyte concentrations
6.5 Hepatic clearance
6.5.1 Hepatic intrinsic clearance
6.5.2 Effect of plasma protein binding on elimination kinetics
6.6 Experimental methods of assessing transfer across biological membranes
6.6.1 Cell culture
6.6.2 Parallel artificial membrane permeability assay
6.6.3 Ussing chambers
6.6.4 Intestinal sacs
6.6.5 In vivo/in situ studies
6.7 Allometric scaling
6.7.1 Refinements to allometric scaling
6.7.2 Practical aspects of allometry
6.7.3 Method of Wajima
6.8 In silico predictions and PBPK modelling
6.9 Microdosing studies
6.10 Translational science
6.11 References
Chapter 7 Disposition of Peptides and Other Biological Molecules
7.1 Introduction
7.2 Chemical aspects
7.2.1 PEGylation
7.3 Assay methods
7.4 Pharmacokinetics
7.4.1 Administration and dosage
7.4.2 Bioequivalence and biosimilarity
7.4.3 Distribution
7.4.4 Metabolism
7.4.5 Excretion
7.5 Plasma kinetics and pharmacodynamics
7.6 Examples of particular interest
7.6.1 Botulinum toxins
7.6.2 Cholecystokinins
7.6.3 Ciclosporin
7.6.4 Cocaine hydrolases
7.6.5 Erythropoietin
7.6.6 Heparin
7.6.7 Mipomersen
7.6.8 Somatotropin
7.6.9 Vasopressin and desmopressin
7.7 References
Chapter 8 Monoclonal Antibodies
8.1 Introduction
8.2 Nomenclature
8.3 Circulation of monoclonal antibodies
8.3.1 Convection
8.3.2 Neonatal Fc receptor
8.3.3 Binding to soluble target antigens
8.4 Pharmaceutical and DMPK aspects
8.4.1 Routes of administration
8.4.2 Distribution and apparent volume of distribution
8.4.3 Metabolism and excretion
8.4.4 Pharmacokinetics
8.4.5 Individual and population pharmacokinetics
8.5 Development of orally administered monoclonal antibodies
8.6 Optimizing pharmacokinetic and pharmacodynamic properties
8.7 Two highlighted early and durable examples
8.7.1 Trastuzumab
8.7.2 Adalimumab
8.8 PBPK modelling
8.9 Antibody–drug conjugates
8.9.1 Payloads
8.9.2 Linkers
8.9.3 Bystander killing
8.9.4 Disposition and pharmacokinetics
8.10 References
Chapter 9 Drug Metabolism and Pharmacokinetics in Veterinary Sciences
9.1 Introduction
9.2 Areas of practice
9.2.1 Companion animal medicine
9.2.2 Treatment of animals of commerce
9.2.3 Zoos and wildlife preserves
9.2.4 Laboratory animal medicine
9.3 Scientific approach including allometric scaling
9.4 Information organized by pharmacokinetic processes
9.4.1 Administration
9.4.2 Absorption
9.4.3 Tissue distribution
9.4.4 Plasma protein binding and transporters
9.4.5 Metabolism
9.4.6 Excretion
9.5 Information organized by species and drugs
9.5.1 Mammals
9.5.2 Fish
9.6 Some drugs unique to veterinary science
9.7 Accidental exposure: toxicology – drugs used by humans that are dangerous to animals
9.7.1 Paracetamol in cats
9.7.2 Xanthines: chocolate in dogs
9.8 Residue analysis
9.9 References
Chapter 10 Factors Affecting Plasma Concentrations: Consideration of Special Populations
10.1 Introduction
10.2 Pharmaceutical factors
10.3 Weight and obesity
10.3.1 Effects of obesity on pharmacokinetics
10.3.2 Dose adjustment in obesity
10.3.3 Oral contraceptives
10.3.4 Gastric bypass surgery
10.3.5 Psychiatric patients
10.4 Food, diet, and nutrition
10.4.1 Diet and nutrition
10.5 Time of day
10.5.1 Circadian rhythms
10.5.2 Absorption
10.5.3 The liver
10.5.4 The kidneys
10.5.5 Intravenous and other injected doses
10.5.6 Pharmacodynamics
10.6 Posture and exercise
10.6.1 Exercise
10.7 Smoking
10.8 References
Chapter 11 Pharmacogenetics, Pharmacogenomics, and Precision Medicine
11.1 Introduction
11.1.1 Terminology
11.2 Methods for the study of pharmacogenetics
11.2.1 Studies in twins
11.2.2 Phenotyping and genotyping
11.3 N-Acetyltransferase
11.3.1 Isoniazid
11.3.2 Sulfonamides
11.3.3 Other drugs
11.3.4 Genotyping N-acetyltransferase
11.4 Plasma cholinesterase
11.4.1 Suxamethonium
11.5 Carboxylesterases
11.6 Cytochrome P450 polymorphisms
11.6.1 Cytochrome 2D6
11.6.2 Cytochrome 2C9
11.6.3 Cytochrome 2C19
11.6.4 Cytochromes 3A4/5
11.6.5 Other cytochrome P450 polymorphisms
11.7 Glucose-6-phosphate dehydrogenase
11.7.1 Glucose-6-phosphate dehydrogenase deficiency
11.7.2 Triggering
11.7.3 Effects on pharmacokinetics
11.8 Alcohol dehydrogenase and acetaldehyde dehydrogenase
11.9 Thiopurine methyltransferase
11.10 Phase 2 enzymes
11.10.1 UDP-glucuronosyltransferases
11.10.2 Sulfotransferases
11.10.3 Glutathione transferases
11.11 Transporters
11.12 Pharmacodynamic differences
11.13 Ethnicity
11.14 Personalized medicine
11.15 References
Chapter 12 Effects of Sex and Pregnancy on Drug Disposition and Pharmacokinetics
12.1 Introduction
12.1.1 Studies in animals
12.2 Effect of sex on human drug disposition and pharmacokinetics
12.2.1 Absorption and bioavailability
12.2.2 Distribution
12.2.3 Metabolism
12.2.4 Excretion
12.2.5 Effects
12.3 Pregnancy
12.3.1 Physiological and biochemical changes
12.3.2 Drug-metabolizing enzymes
12.3.3 Transporters
12.3.4 The foetus
12.4 Hormonal effects
12.4.1 Human oestrogen receptors
12.5 Quality of the data
12.6 References
Chapter 13 Developmental Pharmacology and Age-related Phenomena
13.1 Introduction
13.2 Scientific and regulatory environment in regard to younger and older patients
13.3 Terminology
13.4 Dose adjustment
13.4.1 Body surface area
13.4.2 Relative organ size
13.5 Anatomical and physiological differences
13.5.1 Tissue distribution
13.5.2 Absorptive processes
13.5.3 Protein binding
13.5.4 The blood–brain barrier
13.5.5 Liver function
13.5.6 Renal function
13.5.7 Metabolic and pharmacodynamic phenomena
13.6 Age groups
13.6.1 Neonates and children
13.6.2 Elderly
13.7 Further Examples
13.8 References
Chapter 14 Effects of Disease on Drug Disposition and Pharmacokinetics
14.1 Introduction
14.2 Gastrointestinal disorders and drug absorption
14.2.1 General considerations
14.2.2 Inflammatory conditions of the intestines and coeliac disease
14.3 Congestive heart failure
14.3.1 Altered intestinal function
14.3.2 Altered liver blood flow
14.3.3 Altered rate of metabolism – aminopyrine
14.3.4 Altered route of metabolism – glyceryl trinitrate
14.3.5 Altered clearance – mexilitine
14.3.6 Congestive heart failure plus renal problems – toborinone
14.3.7 Decompensated and treated CHF – torasemide
14.3.8 Oedema
14.4 Liver disease
14.4.1 Pathophysiology
14.4.2 Liver blood flow, binding to plasma proteins, and intrinsic hepatic clearance
14.4.3 Methods of investigation
14.4.4 Selected examples
14.4.5 Drug Effects
14.5 Renal impairment
14.5.1 General considerations
14.5.2 Mathematical approach
14.5.3 Selected examples
14.6 Thyroid disease
14.6.1 General considerations
14.6.2 Examples
14.7 Respiratory Disorders
14.7.1 Methodological issues
14.7.2 Fluticasone
14.7.3 Three further examples
14.8 Assessing pharmacokinetics in special populations
14.9 References
Chapter 15 Role of Stereochemistry in Drug Disposition and Pharmacokinetics
15.1 Introduction
15.1.1 Isomers
15.1.2 Enantiomers: optical isomerism
15.1.3 Cis–trans isomerism
15.1.4 Importance of stereochemistry in pharmacology
15.1.5 Racemization, inversion, and epimerization
15.2 Absorption
15.2.1 Percutaneous absorption
15.2.2 Transporters
15.3 Plasma protein binding
15.3.1 Effect of stereochemistry
15.4 Metabolism
15.4.1 Stereospecific metabolism
15.4.2 Inversion
15.4.3 Chiral to achiral conversion
15.4.4 Insertion of additional chiral centres
15.4.5 Metabolism of achiral to chiral molecules
15.5 Excretion
15.5.1 Renal clearance
15.6 Development and marketing of single isomers
15.6.1 Chiral switch
15.7 References
Chapter 16 Drug Metabolism and Pharmacokinetics in Drug Interactions and Toxicity
16.1 Introduction
16.2 Drug interactions
16.2.1 Terminology
16.2.2 Time action considerations
16.2.3 Absorption
16.2.4 Distribution
16.2.5 Metabolism
16.2.6 Excretion
16.2.7 Homergic interactions
16.2.8 When drug interactions are important
16.2.9 Desirable interactions
16.2.10 Predicting the risk of drug interactions with new chemical entities
16.3 Toxicity
16.3.1 Terminology
16.3.2 Dose–response and time action with special reference to toxicology
16.3.3 Toxicity associated with prolonged exposure to therapeutic doses
16.3.4 Safety studies in new drug discovery
16.3.5 Selected examples
16.4 References
Chapter 17 Drug Monitoring in Therapeutics
17.1 Introduction
17.2 General considerations
17.2.1 Samples and sampling
17.2.2 What should be measured?
17.2.3 Timing of sample collection
17.2.4 Analyses
17.2.5 Reference ranges
17.3 Specific Examples
17.3.1 Antiasthmatic drugs
17.3.2 Anticoagulant drugs
17.3.3 Anticonvulsant drugs
17.3.4 Antidepressant drugs
17.3.5 Antimicrobial agents
17.3.6 Antipsychotic drugs
17.3.7 Cardioactive drugs
17.3.8 Immunosuppressive drugs
17.3.9 Lithium
17.3.10 Therapeutic antibodies
17.3.11 Thyroxine
17.4 Dose adjustment
17.4.1 Gentamicin
17.4.2 Phenytoin
17.5 References
Chapter 18 From Antiquity to the Age of Artificial Intelligence: Reflections on the Past, Present, and Future of Drug Disposition and Pharmacokinetics
18.1 Drug disposition: Historical aspects
18.1.1 Pharmacodynamics
18.1.2 Quantification of drugs
18.1.3 Pharmacokinetic modelling
18.1.4 Drug discovery and development
18.2 Computerization and automation
18.2.1 Computer-aided drug discovery
18.3 Intelligence, intellect, and artificial intelligence in DMPK
18.3.1 Natural and artificial intelligence
18.4 Where are we now and what does the future hold?
18.5 Postscript
18.6 References
Index
EULA