Pharmacokinetics and Metabolism in Drug Design

In this new edition of a bestseller, all the contents have been updated and new material has been added, especially in the areas of toxicity testing and high throughput analysis. The authors, all of them employed at Pfizer in the discovery and development of new active substances, discuss the significant 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.

In this new edition of a bestseller, all the contents have been updated and new material has been added, especially in the areas of toxicity testing and high throughput analysis. The authors, all of them employed at Pfizer in the discovery and development of new active substances, discuss the significant 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.

PHYSICOCHEMISTRYPartition and Distribution Coefficient as Measures of LipophilicityLimitations on the Use of OctanolFurther Understanding of log PAlternative Lipophilicity ScalesComputational Approaches to LipophilicityMembrane Systems to Study Drug BehaviourNEW: Dissolution and SolubilityNEW: Ionisation (pKa)PHARMACOKINETICSIntravenous Administration: Volume of DistributionIntravenous Administration: ClearanceClearance and Half-LifeIntravenous administration: InfusionOral AdministrationRepeated DosesDevelopment of the Unbound (Free) Drug ModelUnbound Drug and Drug ActionUnbound Drug Model and Barriers to EquilibriumSlow Offset CompoundsFactors Governing Unbound Drug ConcentrationABSORPTIONThe Absorption ProcessDissolutionMembrane TransferBarriers to Membrane TransferModels for Absorption EstimationEstimation of Absorption PotentialComputational ApproachesDISTRIBUTIONMembrane Transfer Access to the TargetBrain penetrationVolume of Distribution and DurationDistribution and TmaxCLEARANCEThe Clearance ProcessesRole of Transport Proteins in Drug ClearanceInterplay Between Metabolic and Renal ClearanceRole of Lipophilicity in Drug ClearanceRENAL 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) CLEARANCEFunction of Metabolism (Biotransformation)Cytochrome P450Other oxidative processesOxidative Metablism and Drug DesignNon-Specific EsterasesProdrugs to Aid Membrane TransferEnzymes Catalysing Drug ConjugationStability to Conjugation ProcessesPharmacodynamics and ConjugationTOXICITYToxicity FindingsImportance of dose sizeToxicity of selected compound classesStratification of ToxicityToxicity Prediction - Computational ToxicologyToxicogenomicsEnzyme Induction (CYP3A4) and Drug DesignEnzyme Inhibition and Drug DesignINTERSPECIES SCALINGObjectives of Allometric ScalingAllometric ScalingSpecies Scaling: Adjusting for Maximum Life-Span PotentialSpecies Scaling: Incorporating Differences in Metabolic ClearanceInter-Species Scaling for Clearance by Hepatic UptakeElimination Half-LifeNEW: Scaling to pharmacological effectNEW: Single animal scalingHIGH(ER) THROUGHPUT ADME STUDIESThe HTS TrendDrug Metabolism and Discovery Screening SequencesPhysicochemistryAbsorption / PermeabilityPharmacokineticsNEW: Metabolism and InhibitionNEW: The concept of ADME spaceComputational Approaches in PK and Metabolism PredictionOutlook