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.

InhaltsangabePHYSICOCHEMISTRY 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 HighThroughput 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

Leseprobe

Physicochemistry 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 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 Approaches Distribution Membrane Transfer Access to the Target Brain Penetration Distribution into Tumours Volume of Distribution and Duration Distribution and Tmax 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 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 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 Toxicogenomics Pharmacogenomics 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 Physicochemistry Absorption/Permeability Pharmacokinetics Metabolism and Inhibition The Concept of ADME Space Computational Approaches in PK and Metabolism Outlook