Pharmacokinetics and Metabolism in Drug Design

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.

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.

PHYSICOCHEMISTRYPhysicochemistry and PharmacokineticsPartition and Distribution Coefficients as Measures of LipophilicityLimitations on the Use of 1-OctanolFurther Understanding of logPAlternative Lipophilicity ScalesComputational Systems to Determine LipophilicityMembrane Systems to Study Drug BehaviorDissolution and SolubilityThe BCS Classification and Central Role of PermeabilityPHARMACOKINETICSSetting the SceneIntravenous Administration: Volume of DistributionIntravenous Administration: ClearanceIntravenous Administration: Clearance and Half-lifeIntravenous Administration: InfusionOral AdministrationRepeated DosesDevelopment of the Unbound (Free) Drug ModelUnbound Drug and Drug ActionUnbound Drug Model and Barriers to EquilibriumPharmacodynamic ModelsSlow Offset CompoundsFactors Governing Unbound Drug ConcentrationABSORPTIONThe Absorption ProcessDissolutionMembrane TransferBarriers to Membrane TransferProdrugs to Increase Oral AbsorptionActive TransportModels for Absorption EstimationEstimation of Absorption Potential and other ComputationalDISTRIBUTIONMembrane Transfer Access to the TargetBrain PenetrationCLEARANCEThe Clearance ProcessesRole of Transport Proteins in Drug ClearanceInterplay Between Metabolic and Renal ClearanceRole of Lipophilicity in Drug ClearanceActive MetabolitesBalancing the Rate of Renal and Metabolic clearance and PotencyRENAL CLEARANCEKidney Anatomy and FunctionLipophilicity and Reabsorption by the KidneyEffect of Charge on Renal ClearancePlasma Protein Binding and Renal ClearanceBalancing Renal Clearance and AbsorptionRenal Clearance and Drug DesignMETABOLIC (HEPATIC) CLEARANCESymbolsFunction of Metabolism (Biotransformation)Cytochrome P450Other Oxidative Metabolism ProcessesOxidative Metabolism and Drug DesignNonspecific EsterasesProdrugs to Aid Membrane TransferEnzymes Catalyzing Drug ConjugationStability to Conjugation ProcessesPharmacodynamics and ConjugationTOXICITYToxicity FindingsStructure - Toxicity AnalysesReactive Metabolite Screening in Drug DiscoveryStructural Alerts/Toxicophores in Drug DesignDealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Effect of Daily DoseDealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Competing Detoxication PathwaysStratification of ToxicityToxicity Prediction: Computational ToxicologyToxicogenomicsPharmacogenomicsEnzyme Induction and Drug DesignEnzyme Inhibition and Drug DesignPREDICTING HUMAN PHARMACOKINETICSObjectives of Predicting Human PharmacokineticsAllometric Scaling of Preclinical In Vivo PK ParametersPrediction of Human PK Parameters Using In Vitro DataElimination Half-LifeMoving ForwardADME SCREENINGThe High-Throughput Synthesis and Screening TrendThe Concept of ADME SpaceDrug Metabolism and Discovery Screening SequencesPhysicochemistryAbsorption/PermeabilityMetabolism, Induction, and InhibitionTransportersProtein BindingPharmacokinetics