In this new edition of a bestseller, all the contents have been brought up-to-date by addressing current standards and best practices in the assessment and prediction of ADMET properties. Although the previous chapter layout has been retained, substantial revisions have been made, with new topics such as pro-drugs, active metabolites and transporters covered in detail in a manner useful to the Drug Discovery scientist. The authors discuss the parameters and processes important for the absorption, distribution and retention of drug compounds in the body, plus the potential problems created by their transformation into toxic byproducts.
Uniquely comprehensive, the book relates physicochemistry and chemical structure to pharmacokinetic properties and ultimately drug efficacy and safety.
While aimed at all those dealing professionally with the development and application of pharmaceutical substances, the readily comprehensible style makes this book equally suitable for students of pharmacy and related subjects.
New to This Edition
- The third edition features several new subchapters on novel approaches that are currently in the focus of pharmaceutical scientists.
- In the Physicochemistry chapter, new sections on membrane systems and on the BCS classification have been added. The Absorption chapter now also discusses active transports and prodrugs for increased oral absorption.
- Distribution of drugs into tumors and active metabolites are now discussed in chapters 4 and 5. The toxicity chapter has been completely rewritten to cover the current risk assessment-driven approach in the field. Chapter 9 (Inter-species scaling) has been replaced with a new chapter on the prediction of human pharmacokinetics that shows the current integrated in vitro/in vivo/in silico approach that has become the standard in the industry.
- Data in figures and tables have been updated where appropriate, and new references have been added.
Table of Contents
- Physicochemistry and Pharmacokinetics
- Partition and Distribution Coefficient as Measures of Lipophilicity
- Limitations on the Use of 1-Octanol
- Further Understanding of log P
- Alternative Lipophilicity Scales
- Membrane Systems to Study Drug Behaviour
- Dissolution and Solubility
- The BCS Classification and Central Role of Permeability
- Setting the Scene
- Intravenous Administration: Volume of Distribution
- Intravenous Administration: Clearance
- Intravenous Administration: Clearance and Half-life
- Intravenous Administration: Infusion
- Oral Administration
- Repeated Doses
- Development of the Unbound (Free) Drug Model
- Unbound Drug and Drug Action
- Unbound Drug Model and Barriers to Equilibrium
- Pharmacodynamic Models
- Slow Offset Compounds
- Factors Governing Unbound Drug Concentration
- The Absorption Process
- Membrane Transfer
- Barriers to Membrane Transfer
- Prodrugs to Increase Oral Absorption
- Active Transport
- Models for Absorption Estimation
- Estimation of Absorption Potential and Other Computational Approaches
- Membrane Transfer Access to the Target
- Brain Penetration
- Distribution into Tumours
- Volume of Distribution and Duration
- Distribution and Tmax
- The Clearance Processes
- Role of Transport Proteins in Drug Clearance
- Interplay Between Metabolic and Renal Clearance
- Role of Lipophilicity in Drug Clearance
- Active Metabolites
- Balancing the Rate of Renal and Metabolic Clearance and Potency
- Renal Clearance
- Kidney Anatomy and Function
- Lipophilicity and Reabsorption by the Kidney
- Effect of Charge on Renal Clearance
- Plasma Protein Binding and Renal Clearance
- Balancing Renal Clearance and Absorption
- Renal Clearance and Drug Design
- Metabolic (Hepatic) Clearance
- Function of Metabolism (Biotransformation)
- Cytochrome P450
- Other Oxidative Metabolism Processes
- Oxidative Metabolism and Drug Design
- Non-Specific Esterases
- Prodrugs to Aid Membrane Transfer
- Enzymes Catalysing Drug Conjugation
- Stability to Conjugation Processes
- Pharmacodynamics and Conjugation
- Toxicity Findings
- Structure Toxicity Analyses
- Reactive Metabolite Screening in Drug Discovery
- Structural Alerts /
- Toxicophores in Drug Design
- Risk Assessment Strategies ? Effect of Daily Dose
- Risk Assessment Strategies ? Competing Detoxication Pathways
- Stratification of Toxicity
- Toxicity Prediction and Computational Toxicology
- Enzyme Induction and Drug Design
- Enzyme Inhibition and Drug Design
- Predicting Human Pharmacokinetics
- Objectives of Predicting Human Pharmacokinetics
- Allometric Scaling of Pre-Clinical In Vivo PK parameters
- Prediction of Human PK Parameters Using In Vitro Data
- Elimination Half-Life
- High(er) Throughput ADME Studies
- The High-Throughput Screening (HTS) Trend
- Drug Metabolism and Discovery Screening Sequences
- Metabolism and Inhibition
- The Concept of ADME Space
- Computational Approaches in PK and Metabolism
Dennis Smith has worked in the pharmaceutical industry for more than 30 years since gaining his Ph.D. from the University of Manchester (UK). Working at Pfizer Global R&D at Sandwich for the past 20 years, he was named Vice President for Pharmacokinetics, Dynamics and Metabolism. His research interests and publications span all aspects of drug discovery and development, particularly where drug metabolism impacts on the design of more efficacious and safer drugs.
Charlotte Allerton is the Pharmacokinetics, Dynamics and Metabolism Site Lead for Pfizer, Sandwich, UK. Charlotte obtained her first degree at the University of Nottingham, and a MPhil from the University of Cambridge Chemistry Department. Charlotte initially spent 14 years in Medicinal Chemistry at Pfizer in Sandwich working across a range of disease areas, before joining the Pharmacokinetics, Dynamics and Metabolism (PDM) department in 2007 as the Genitourinary Therapeutic Area Lead. In 2008 Charlotte became the PDM Sandwich Site Lead, covering a portfolio of anti-viral, allergy and respiratory, pain and internal medicine drug discovery programmes.
Amit Kalgutkar received his academic degrees from the University of Bombay (India) and from Virginia Polytechnic Institute (USA). Joining Pfizer in 1999, he is currently a Research Fellow in the Pharmacokinetics, Dynamics and Metabolism Department at Pfizer (Groton Laboratories). He is also an adjunct faculty member in the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island.
Han van de Waterbeemd studied Chemistry at the Technival University of Eindhoven and did a Ph.D. in Medicinal Chemistry at the University of Leiden, The Netherlands. In his pharmaceutical career he worked for Roche, Pfizer and Astra-Zeneca. His research interests include the role of molecular properties in drug disposition and modeling of ADMET properties.
Don Walker has a degree in Biochemistry from the University of London (UK). He joined the Drug Metabolism Department at Pfizer in Sandwich in 1986 and since then has contributed to the drug metabolism and pharmacokinetic evaluations on several drug discovery and development projects.