Beschreibung
InhaltsangabeA. 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 Transpo
