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Pharmacokinetics and Metabolism in Drug Design, 3rd Edition

Pharmacokinetics and Metabolism in Drug Design, 3rd Edition

Dennis A. Smith (Editor), Charlotte Allerton (Editor), Amit S. Kalgutkar (Editor), Han van de Waterbeemd (Editor), Don K. Walker (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)

ISBN: 978-3-527-32954-0

May 2012

268 pages

In Stock



In this new edition of a bestseller, all the contents have been brought upto-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.

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. Uniquely comprehensive, the book relates physicochemistry and chemical structure to pharmacokinetic properties and ultimately drug efficacy and safety.
Physicochemistry and Pharmacokinetics
Partition and Distribution Coefficients as Measures of Lipophilicity
Limitations on the Use of 1-Octanol
Further Understanding of logP
Alternative Lipophilicity Scales
Computational Systems to Determine Lipophilicity
Membrane Systems to Study Drug Behavior
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

Membrane Transfer Access to the Target
Brain Penetration

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

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

Function of Metabolism (Biotransformation)
Cytochrome P450
Other Oxidative Metabolism Processes
Oxidative Metabolism and Drug Design
Nonspecific Esterases
Prodrugs to Aid Membrane Transfer
Enzymes Catalyzing 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
Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies -
Effect of Daily Dose
Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies -
Competing Detoxication Pathways
Stratification of Toxicity
Toxicity Prediction: Computational Toxicology
Enzyme Induction and Drug Design
Enzyme Inhibition and Drug Design

Objectives of Predicting Human Pharmacokinetics
Allometric Scaling of Preclinical In Vivo PK Parameters
Prediction of Human PK Parameters Using In Vitro Data
Elimination Half-Life
Moving Forward

The High-Throughput Synthesis and Screening Trend
The Concept of ADME Space
Drug Metabolism and Discovery Screening Sequences
Metabolism, Induction, and Inhibition
Protein Binding
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.