Pharmacokinetics and Metabolism in Drug Design / Edition 3

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Overview

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. New chapters on prodrugs, antitumor drugs and active metabolites, among other topics, have been added. The authors, all of them employed at Pfizer in the discovery and development of new active substances, 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. They cover everything from the fundamental principles right up to the impact of pharmacokinetic parameters on the discovery of new drugs. 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.

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Product Details

Meet the Author

Dennis Smith worked in the pharmaceutical industry for more than 30years since gaining his PhD from the University of Manchester (UK).He worked at Pfizer Global R & D at Sandwich for 24 years, withthe role of Vice President for Pharmacokinetics, Dynamics andMetabolism. During his career he directly contributed to theDiscovery and Development of eight NCEs. Now retired he is stillactive in an academic
(Visiting Professor, University of Liverpool ) and in an advisorycapacity. His research interests and publications span all aspectsof drug discovery and development, particularly where drugmetabolism impacts on the design of more efficacious and saferdrugs.

Charlotte Allerton obtained her first degree in chemistry from theUniversity of Nottingham, and a MPhil in organic chemistry from theUniversity of Cambridge. She joined the Medicinal Chemistrydepartment in Pfizer at Sandwich in 1993 and worked across a rangeof disease areas, before joining the Pharmacokinetics, Dynamics andMetabolism (PDM) department in 2007. In 2008 Charlotte Allertonbecame the PDM Sandwich Site Lead.

Amit Kalgutkar received his PhD in organic chemistry from VirginiaPolytechnic Institute (USA) and conducted a post-doctoralfellowship at the Department of Biochemistry, Vanderbilt UniversitySchool of Medicine. He joined Pfizer in 1999, where he is currentlya Research Fellow in the Drug Metabolism Group (GrotonLaboratories). He is also an adjunct Professor in the Department ofBiomedical and Pharmaceutical Sciences, University of RhodeIsland.

Han van de Waterbeemd studied physical organic chemistry at theTechnical University of Eindhoven and did a PhD in medicinalchemistry at the University of Leiden, The Netherlands. In hispharmaceutical career he worked for Roche, Pfizer and AstraZeneca.His research interests include the role of molecular properties indrug disposition and computational modeling of ADMETproperties.

DonWalker obtained a degree in biochemistry from the University ofLondon (UK). He worked for Pfizer for 24 years in thePharmacokinetics, Dynamics and Metabolism Department contributingscientific leadership to the drug metabolism and pharmacokineticevaluations on many drug discovery and development projects acrossa range of therapeutic areas including cardiovascular, allergy andrespiratory, anti-infectives and sexual health. Following hisretirement in 2010 he has continued to provide occasionalconsulting and lecturing in the field of metabolism andpharmacokinetics.

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Table of Contents

PHYSICOCHEMISTRY
Physicochemistry and Pharmacokinetics
Partition and Distribution Coefficients as Measures ofLipophilicity
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

PHARMACOKINETICS
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

ABSORPTION
The Absorption Process
Dissolution
Membrane Transfer
Barriers to Membrane Transfer
Prodrugs to Increase Oral Absorption
Active Transport
Models for Absorption Estimation
Estimation of Absorption Potential and other Computational

DISTRIBUTION
Membrane Transfer Access to the Target
Brain Penetration

CLEARANCE
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
Symbols
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
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: RiskAssessment Strategies -
Effect of Daily Dose
Dealing with Reactive Metabolite Positives in Drug Discovery: RiskAssessment Strategies -
Competing Detoxication Pathways
Stratification of Toxicity
Toxicity Prediction: Computational Toxicology
Toxicogenomics
Pharmacogenomics
Enzyme Induction and Drug Design
Enzyme Inhibition and Drug Design

PREDICTING HUMAN PHARMACOKINETICS
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

ADME SCREENING
The High-Throughput Synthesis and Screening Trend
The Concept of ADME Space
Drug Metabolism and Discovery Screening Sequences
Physicochemistry
Absorption/Permeability
Metabolism, Induction, and Inhibition
Transporters
Protein Binding
Pharmacokinetics

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