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