A compilation of researchers' experience in the areas of bioanalysis, pharmacokinetics, and drug metabolism, to present an up-to-date and comprehensive treatise on the application of these and related technologies in drug discovery, development, and clinical use. Contents cover descriptions of analytical methods, in vitro metabolism technology and membrane transport, reappraisal of classical pharmacokinetic problems, and the time course of drug action. The book concludes with a description of PET and imaging methods in pharmacokinetics and an appendix containing a critical appraisal of computer methods and pharmacokinetic software available for PCs.
Inhalt
A. Introduction.- 1 Role of Pharmacokinetics in Drug Discovery and Development.- A. Historical Background.- B. Regulatory Submissions.- C. The Process.- D. Discovery.- E. Preclinical Development.- I. Toxicology and Toxicokinetics.- II. Pharmacokinetic - Pharmacodynamic Relationships.- III. Interactions.- F. Clinical Development.- I. Phase 1.- II. Phase 2.- III. Phase 3.- IV. Interactions.- V. Regulatory Submissions.- G. Postsubmission and Postmarketing Studies.- H. Summary.- References.- B. Analytical Methods.- 2 Contemporary Aspects of Radioimmunoassay Development for Drug Analysis.- A. Introduction.- B. Synthesis of Drug Derivatives for Immunogen Preparation.- I. Coupling of Hapten Carboxyl Group to Carrier Protein.- II. Addition of Carboxyl to Existing Functional Group.- III. Addition of a Functional Group for Bridge to Carboxylic Acid.- IV. Altering the Basic Structure of the Hapten.- C. Immunogen Preparation.- I. Hapten-Carrier Protein Ratios.- II. Carrier Protein Characteristics.- D. Immunization Considerations.- I. Species Effects.- II. Use of Adjuvants.- III. Immunization Sites and Schedules.- E. Matrix Effects of Biological Fluids.- I. Methods for Sample Matrix Effect Elimination.- 1. Filtration/Precipitation of Protein.- 2. Solvent Extraction.- 3. Solid Phase Chromatographic Extraction.- 4. High-Performance Liquid Chromatographic Sample Preparation.- II. Elimination of Sample Matrix Effect by Sample Size.- F. The Suitability of Radioimmunoassay for Drug Analysis.- References.- 3 Mass Spectrometry in Drug Disposition and Pharmacokinetics.- A. Introduction.- B. Ionization Techniques.- I. Electron Ionization.- II. Positive Chemical Ionization.- III. Electron Capture Negative Chemical Ionization.- IV. Liquid Secondary Ion/Fast Atom Bombardment.- V. Thermospray.- VI. Atmospheric Pressure Ionization.- VII. Collision-Induced Dissociation.- C. Chromatographic Techniques.- I. Gas Chromatography/Mass Spectrometry.- II. Liquid Chromatography /Mass Spectrometry.- D. Metabolism Studies.- I. In Vitro Studies.- II. In Vivo Studies in Animal Models.- III. In Vivo Studies in Humans.- E. Pharmacokinetic Studies.- I. Introduction.- II. Animal Models.- III. Humans.- F. Summary.- References.- 4 Analytical Methods for Biotechnology Products.- A. Introduction.- B. Methods.- I. Radiolabels.- 1. Selection of Radiolabel.- 2. Whole-Body Autoradiography.- 3. Radiolabel Realities.- II. Immunoassays.- 1. Enzyme Immunoassays.- 2. Radiolabel-Based Immunoassays.- 3. Immunoassay Limitations.- 4. Immunoassay Interferences.- III. Bioassays.- IV. Other Immunological Techniques.- V. Chromatography.- VI. Electrophoretic Techniques.- VII. Mass Spectrometry.- C. Conclusions.- References.- C. In Vitro Methods-Protein and Tissue Binding.- 5 Metabolism: Scaling-up from In Vitro to Organ and Whole Body.- A. Introduction.- B. Correlation of In Vitro and In Vivo Data.- I. Concept of Organ Clearance.- 1. Hepatic Clearance Models.- 2. In Vitro-Organ Correlations.- II. Concept of Total Body Clearance.- 1. From In Vitro to In Vivo: Compartmental Modeling.- 2. From In Vitro to In Vivo: Physiological Modeling.- 3. From Perfused Organs to In Vivo.- C. Poor Correlations Between In Vitro and Perfused Organs.- I. Inadequacy of In Vitro Estimates.- 1. Estimation of Enzymatic Parameters.- 2. Multiplicity of Enzymes.- 3. Membrane-Bound Enzymes.- 4. Time-Dependent Kinetics.- II. Structural Considerations and Physiological Variables.- 1. Flow.- 2. Protein Binding.- 3. Transmembrane Limitation.- 4. Cosubstrate.- 5. Acinar Heterogeneity.- D. Reasons for Poor Correlations Between In Vitro, Perfused Organs, and In Vivo.- E. Conclusions.- References.- 6 Gastrointestinal Transport of Peptide and Protein Drugs and Prodrugs.- A. Introduction.- B. Mucosal Cell Absorption.- I. Paracellular Absorption.- II. Transcellular Absorption.- 1. Simple Diffusion.- 2. Carrier-Mediated Process.- 3. Endocytosis.- C. Mucosal Cell Transport of Peptide Drugs.- I. Characteristics of Small Peptide Transport.- 1. Substrate Structural Requirements.- II. Carrier-Mediated Transport of Peptide Drugs.- 1. ?-Lactam Antibiotics.- 2. ACE Inhibitors.- D. Estimating Extent of Drug Absorption.- I. Fraction of Dose Absorbed - Permeability Correlation.- II. Comparison of Passive and Carrier-Mediated Transport.- E. Peptide Prodrug Approaches to Improving Intestinal Absorption.- I. Peptide Prodrugs of ?-Methyldopa.- II. Peptide Prodrug Approaches for Acidic Drugs.- III. Other Peptide Prodrugs.- F. Summary.- References.- D. Classical Problems.- 7 Stereoselectivity in Metabolic Reactions of Toxication and Detoxication.- A. Introduction.- B. Principles of Stereoselective Xenobiotic Metabolism.- I. Chiral Recognition and Stereoselective Processes in Xenobiotic Metabolism and Disposition.- II. Substrate Stereoselectivity and Product Stereoselectivity.- III. Substrate-Product Stereoselectivity.- IV. Relevance to Molecular Toxicology.- C. Toxicologically Relevant Examples of Stereoselective Metabolism.- I. Introduction.- II. Substrate Stereoselectivity in Drug Oxidation: Disopyramide and Mianserin.- III. Product Stereoselectivity in Drug Oxidation and Reduction: Phenytoin and Nabilone.- IV. Substrate Stereoselectivity in Xenobiotic Conjugation: Fenvalerate.- D. The Case of Profens.- I. Metabolic Chiral Inversion: In Vivo and In Vitro Studies.- II. Mechanism of Inversion.- III. Toxicological Consequences of Chiral Inversion.- E. Conclusion.- References.- 8 Interethnic Differences in Drug Disposition and Response: Relevance for Drug Development, Licensing, and Registration.- A. Introduction.- B. Case Reports.- I. Unexpected Behavior.- II. A Biopharmaceutical Dilemma.- III. The Drug Which Did Not Become a Case.- IV. The Drug Which Is Not a Case.- C. Basic Concepts and Definitions.- D. Integration of Pharmacokinetic, Pharmacodynamic, and Toxicokinetic Principles in Drug Development.- I. The Conceptual Framework.- II. Preclinical Studies.- III. Phase 1 Studies.- IV. Phase 2 Studies.- V. Phase 3 Clinical Studies.- VI. Regulatory Considerations.- VII. Interethnic Differences in Drug Behavior and Action and PK/PD Integration.- E. Preclinical Studies.- F. Phase 1 Studies and Interethnic Differences.- I. Investigational Pharmacokinetics.- II. Investigational Pharmacodynamics.- III. Bioavailability Investigations.- IV. Bioequivalence Studies.- G. Phase 2 Studies.- H. Phase 3 Studies.- I. Phase 4 Studies in the Context of Drug Product Licensing.- I. Pharmacoanthropological Considerations.- II. Studies in Healthy Volunteers.- III. Studies in Patients.- J. Conclusions.- References.- Appendix. Selected References on Interethnic Differences in Drug Kinetics.- 9 Clinical Relevance of Pharmacogenetics.- A. Introduction.- B. The Genetic Polymorphism of the Sparteine/Debrisoquine Oxidation.- I. Molecular Mechanisms of the Sparteine/Debrisoquine Polymorphism.- II. Clinical Consequences of the Sparteine/Debrisoquine Polymorphism and Assignment of Genotype or Phenotype.- C. The Genetic Polymorphism of Mephenytoin Oxidation.- I. Molecular Mechanisms of the Mephenytoin Polymorphism.- II. Clinical Consequences of Polymorphic Mephenytoin Oxidation and Assignment of Genotype or Phenotype.- D. The Genetic Polymorphism of N-Acetylation.- I. Molecular Mechanisms of Polymorphic N-Acetylation.- II. Clinical Conseque…