Pharmacokinetics and Metabolism in Drug Design

Pharmacokinetics and Metabolism in Drug Design

Hardback Methods and Principles in Medicinal Chemistry

By (author) Douglas A. Smith, By (author) Charlotte Allerton, By (author) Han Walker, By (author) Han Van De Waterbeemd, By (author) Amit S. Kalgutkar, By (author) Don K. Walker, Series edited by Hugo Kubinyi, Series edited by Raimund Mannhold, Series edited by Gerd Folkers

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  • Publisher: Wiley-VCH Verlag GmbH
  • Format: Hardback | 268 pages
  • Dimensions: 174mm x 246mm x 18mm | 662g
  • Publication date: 5 June 2012
  • Publication City/Country: Weinheim
  • ISBN 10: 3527329544
  • ISBN 13: 9783527329540
  • Edition: 3, Revised
  • Edition statement: 3rd Revised edition
  • Illustrations note: 160 schwarz-weiße Abbildungen, 20 schwarz-weiße Tabellen
  • Sales rank: 1,237,215

Product description

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. 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.

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Author information

Dennis Smith worked in the pharmaceutical industry for more than 30 years since gaining his PhD from the University of Manchester (UK). He worked at Pfizer Global R & D at Sandwich for 24 years, with the role of Vice President for Pharmacokinetics, Dynamics and Metabolism. During his career he directly contributed to the Discovery and Development of eight NCEs. Now retired he is still active in an academic (Visiting Professor, University of Liverpool ) and in an advisory capacity. 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 obtained her first degree in chemistry from the University of Nottingham, and a MPhil in organic chemistry from the University of Cambridge. She joined the Medicinal Chemistry department in Pfizer at Sandwich in 1993 and worked across a range of disease areas, before joining the Pharmacokinetics, Dynamics and Metabolism (PDM) department in 2007. In 2008 Charlotte Allerton became the PDM Sandwich Site Lead. Amit Kalgutkar received his PhD in organic chemistry from Virginia Polytechnic Institute (USA) and conducted a post-doctoral fellowship at the Department of Biochemistry, Vanderbilt University School of Medicine. He joined Pfizer in 1999, where he is currently a Research Fellow in the Drug Metabolism Group (Groton Laboratories). He is also an adjunct Professor in the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island. Han van de Waterbeemd studied physical organic chemistry at the Technical University of Eindhoven and did a PhD in medicinal chemistry at the University of Leiden, The Netherlands. In his pharmaceutical career he worked for Roche, Pfizer and AstraZeneca. His research interests include the role of molecular properties in drug disposition and computational modeling of ADMET properties. DonWalker obtained a degree in biochemistry from the University of London (UK). He worked for Pfizer for 24 years in the Pharmacokinetics, Dynamics and Metabolism Department contributing scientific leadership to the drug metabolism and pharmacokinetic evaluations on many drug discovery and development projects across a range of therapeutic areas including cardiovascular, allergy and respiratory, anti-infectives and sexual health. Following his retirement in 2010 he has continued to provide occasional consulting and lecturing in the field of metabolism and pharmacokinetics.

Back cover copy

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.

Table of contents

PHYSICOCHEMISTRY 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 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: 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 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