Pharmacokinetics of Drugs
(Sprache: Englisch)
The author of this Foreword has recently retired after spending 25 years in academia and 15 years in the pharmaceutical industry. Most of this time has been spent following and, hopefully in some instances, contributing to advancement of the discipline of...
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The author of this Foreword has recently retired after spending 25 years in academia and 15 years in the pharmaceutical industry. Most of this time has been spent following and, hopefully in some instances, contributing to advancement of the discipline of pharmacokinetics. During the last 40 years, pharmacokinetics has grown from a fledgling in the 1950s to an adult in the 1990s. The late development of the discipline of pharmacokinetics, relative to other disciplines such as chemistry, bio chemistry, and pharmacology, probably stems both from general ignorance of the importance of the time course of concentration-effect relationships in drug therapy and from our technical inability to do anything about it had we been more enlightened. Just as the end of the historical dark ages had to await the beginning of the Carolingian revival, so the end of the pharma co kinetic dark age had to await the discovery of adequate analytical methods and also an intellectual leap of faith to accept that drug action is in some way dependent on receptor site occupancy, and therefore on drug con centration. The recent evolution of pharmacokinetics has occurred in three phases which may be identified as those of discovery, stabilization, and rationaliz ation. The discovery phase, which occurred in the 1950s and 1960s, esta blished the mathematics and concepts of "modern" pharmacokinetics and sought areas of application, ranging from model-independent methods, through compartment approaches, to complex physiological models.
Inhaltsverzeichnis zu „Pharmacokinetics of Drugs “
A. Introduction1 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
... mehr
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 Consequences of Polymorphic Acetylation and Assignment of Genotype or Phenotype
E. Genetic Polymorphisms and Drug Development
F. Genetic Polymorphisms and Drug Interactions
G. Conclusions
- References
10 Role of Environmental Factors in the Pharmacokinetics of Drugs: Considerations with Respect to Animal Models, P-450 Enzymes, and Probe Drugs
A. Introduction
B. Relevant Environmental Factors
I. What Are "Relevant" Environmental Factors?
II. Examples
1. Cigarette Smoking
2. Alcohol Drinking
3. Drugs
4. Occupational Chemicals
5. Other Factors
C. Animal Models
I. Environmental Regulation of P-450 Isoforms in the Rat
II. Similarities and Differences Between Species
III. Reasons for Interspecies Differences
IV. Model Experiments in Animals
D. Important (Iso)enzymes in Man
I. P-450 Enzymes
1. P-450 1A1
2. P-450 1A2
3. P-450 2A6
4. P-450 2B6
5. P-450 2C
6. P-450 2D6
7. P-450 2E1
8. P-450 3A
II. Conjugative Enzymes
III. Heterologous Expression Systems
E. Probe Drugs
I. The Probe Drug Concept
1. The "Ideal" Probe Drug
2. "General" vs "Specific" Probe Drugs
II. Importance of Enzyme Specificity
III. Selected Probe Drugs
1. Antipyrine
2. Aminopyrine
3. Caffeine
4. Theophylline
5. Nifedipine
6. Barbiturates
7. Tolbutamide
8. Warfarin
9. Other Potential Probes
10. Endogenous Probes
IV. Cocktail Approach
F. Practical Considerations for Human Studies
G. Final Considerations
- References
11 Time Course of Drug Effect
A. Introduction
I. Why Prediction of Effect Over Time Is Important
1. Drug Development
2. Dosage Individualization
B. Methodological Considerations Relevant to Measuring Effects
I. Standardization
II. Continuous Scale Versus Discrete Response
III. Baseline and Placebo Effect
C. Pharmacokinetic-Pharmacodynamic Models
I. Pharmacokinetics
II. Kietics of Receptor Binding
III. Steady-State Pharmacodynamic Models
IV. Non-Steady-State Pharmacodynamic Models
1. Effect Compartment
2. Physiological Mediator
V. Placebo Effect
1. Pharmacokinetics
2. Placebo Effect Model
3. Placebo Efficacy
VI. Disease Time Course and Drug Effects
1. Disease Time Course
2. Models of Drug Effect on Disease Progression
VII. Tolerance
1. Pharmacokinetics
2. Pharmacodynamics
D. Conclusion
- References
E. Future Trends in Pharmacokinetics
12 Biotechnology Products
A. Introduction
B. Pharmacokinetic/Pharmacodynamic Studies
I. Oligonucleotides
II. Proteins
1. Insulin
2. Relaxin
3. Interferon-?-2A
C. Regimen-Dependent Effects
I. Growth Hormone
II. Parathyroid Hormone
III. Tissue Plasminogen Activator
D. Binding Proteins/Inhibitors
I. Growth Hormone
II. Tissue Plasminogen Activator
III. Insulin-like Growth Factor-I
IV. Deoxyribonuclease
E. Catabolism of Biotechnology Products
I. Catabolism at Extravascular Sites of Administration
F. Drug Interactions
- References
13 Peptide and Protein Drugs
A. Introduction
I. Differences Between the Pharmacokinetics of Peptides/Proteins and Other Drugs
II. Scope of This Review
B. Pharmacokinetic Mechanisms
I. Distribution in the Body
II. Inactivation and Elimination
1. Glomerular Filtration
2. Peptidolysis
3. Receptor-Mediated Clearance
III. Uptake from Site of Administration
1. Subcutaneous or Intramuscular Injection
2. Intranasal Administration
3. Oral or Rectal Administration
IV. Pharmacokinetic Behavior Resulting from the Distribution and Elimination Processes
C. Experimental Approaches
I. Analytical Methods
1. Ex Vivo Bioassay
2. Radioimmunoassay
3. Radiolabeling
4. High-Performance Liquid Chromatography
5. Radiosequencing
II. Plasma Pharmacokinetics
1. Intravenous Bolus and Infusion Studies
2. Methods of Assaying Samples
3. Information That can Be Derived from Plasma Pharmacokinetic Studies
4. Use of Organ Ablation to Locate Clearance Sites
III. Distribution, Metabolism, and Elimination
1. Typical Experiments and Results
2. Difficulties in Interpreting Results
3. Problems in Carrying Out Drug Elimination Studies
IV. Organ Clearance
V. Receptor-Mediated Clearance Kinetics
VI. Absorption (Bioavailability) Measurement
1. Oral Route
2. Nasal Route
D. Conclusions
- References
14 Toxicokinetics
A. Introduction
B. Principles of Toxicokinetics
C. Bioanalytical Procedures to Support Toxicokinetic Studies
D. Dose-Plasma Concentration Relationship (Linear-Nonlinear Kinetics)
E. Changes in Concentrations upon Multiple Dosing
F. Designing Troubleshooting Studies to Explain Aberrant Data
I. Absorption Issues
1. Dose Proportionality
2. Effect of Diet
3. Effect of Vehicles
II. Metabolism Issues
1. Enzyme Induction
2. Effect of Age
3. Sex Dependency
G. Species Comparisons and Interspecies (Allometric) Scaling
H. Utilization of Pharmacokinetic/Toxicokinetic Data in the Design of Early Clinical Trials
- References
15 The Population Approach: Rationale, Methods, and Applications in Clinical Pharmacology and Drug Development
A. Introduction
B. Rationale
I. "Population Studies" in Large Samples of Subjects
II. Controlled Experimental Studies in Small Groups
III. The Population Approach
C. An Overview of Statistical Methodology for Model-Based Population Analysis
I. Population Model
II. Population Methods for Data Analysis
III. Synthesis
D. Current Experience with the Population Approach and Its Applications to Drug Therapy
I. Introduction
II. Detection of Patient Groups with Altered Kinetics
III. Design of Optimum A Priori Dosage Regimen
IV. Bayesian Estimation of Individual Pharmacokinetic Parameters
V. Recent Novel Applications of Nonlinear Mixed Effects Models to Other Drug-Related Areas
E. Problems and Issues?
I. Misconceptions
II. Some Practical Problems
1. Reliability of Data and Analysis
2. Methodological Issues
III. Validation of the Results
F. Integration of the Population Approach into Clinical Drug Development
I. Introduction
II. Early Human Studies (Phase I)
III. Early Clinical Studies (Phase II)
IV. Clinical Trials (Late Phase II, Phase III)
V. Late Clinical Trials (Late Phase III, Phase IV)
G. Concluding Remarks
- References
F. Impact of New Methods on Pharmacokinetics
16 Contribution of Positron Emission Tomography to Pharmacokinetic Studies
A. Introduction
B. Positron Emitters
C. Drug Labeling - Radiochemistry
D. Positron Emission Tomography
E. Direct Radiolabeled Drug Studies
I. Drug Distribution
II. Drug-Drug and Drug-Nutrient Interactions
III. Drug-Receptor Interactions
1. Tranquilizers
2. Neuroleptics
F. Indirect Radioactive Pharmacokinetic Studies
G. Kinetic Modeling with PET
I. A Two-Compartment Model: the [15O] Water Model
II. A Three-Compartment Linear Model: the [18F] Fluorodeoxyglucose Model
III. A Multicompartment Nonlinear Model: the Ligand- Receptor Model
IV. Modeling Using Simplified Models
V. Modeling Using the Multi-injection Approach
H. Conclusion
- References
17 In Vivo Imaging in Drug Discovery and Design
A. Introduction
B. Pharmacokinetics
I. Antimicrobial Agents
1. Erythromycin
2. Fluconazole
II. Antineoplastic Agents
1. Platinum Compounds
2. 5-Fluorouracil
III. Neuroleptics
IV. Angiotensin-Converting Enzyme Inhibitors
V. Nuclear Magnetic Resonance
C. Pharmacodynamics
I. Cardiovascular
1. Ventricular Function
2. Blood Volume
3. Cardiac Output
II. Renal Perfusion and Function
III. Antineoplastic Agents
IV. Liver Function
V. Intestinal Function
VI. Antimicrobial Agents
VII. Nuclear Magnetic Resonance
D. Summary
- References
G. Appendix
18 Considerations on Data Analysis Using Computer Methods and Currently Available Software for Personal Computers
A. Introduction
B. Program Features and Requirements
I. Data Entry
II. Pharmacokinetic Model Specification
1. Compartmental Models
2. Noncompartmental Approach
3. Pharmacodynamic Models
4. Absorption Kinetics and Bioavailability Studies
5. Urinary Data Analysis
6. Population Pharmacokinetics
7. Calculation of Individual Dosage Regimen
III. Error Model specification
IV. Parameter Estimation
1. Least-Squares and Maximum Likelihood Estimators
2. Linear Equations
3. Nonlinear Equations
V. Confidence Limits on Estimated Parameters
VI. Statistical Measures of Goodness of Fit
VII. Solving Systems of Differential Equations
VIII. Graphic Display of Results
IX. Printing and Plotting Results
X. User Interface and Documentation
XI. Hardware and Software Requirements
C. Directory of Surveyed Software
D. Conclusion
- References
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 Consequences of Polymorphic Acetylation and Assignment of Genotype or Phenotype
E. Genetic Polymorphisms and Drug Development
F. Genetic Polymorphisms and Drug Interactions
G. Conclusions
- References
10 Role of Environmental Factors in the Pharmacokinetics of Drugs: Considerations with Respect to Animal Models, P-450 Enzymes, and Probe Drugs
A. Introduction
B. Relevant Environmental Factors
I. What Are "Relevant" Environmental Factors?
II. Examples
1. Cigarette Smoking
2. Alcohol Drinking
3. Drugs
4. Occupational Chemicals
5. Other Factors
C. Animal Models
I. Environmental Regulation of P-450 Isoforms in the Rat
II. Similarities and Differences Between Species
III. Reasons for Interspecies Differences
IV. Model Experiments in Animals
D. Important (Iso)enzymes in Man
I. P-450 Enzymes
1. P-450 1A1
2. P-450 1A2
3. P-450 2A6
4. P-450 2B6
5. P-450 2C
6. P-450 2D6
7. P-450 2E1
8. P-450 3A
II. Conjugative Enzymes
III. Heterologous Expression Systems
E. Probe Drugs
I. The Probe Drug Concept
1. The "Ideal" Probe Drug
2. "General" vs "Specific" Probe Drugs
II. Importance of Enzyme Specificity
III. Selected Probe Drugs
1. Antipyrine
2. Aminopyrine
3. Caffeine
4. Theophylline
5. Nifedipine
6. Barbiturates
7. Tolbutamide
8. Warfarin
9. Other Potential Probes
10. Endogenous Probes
IV. Cocktail Approach
F. Practical Considerations for Human Studies
G. Final Considerations
- References
11 Time Course of Drug Effect
A. Introduction
I. Why Prediction of Effect Over Time Is Important
1. Drug Development
2. Dosage Individualization
B. Methodological Considerations Relevant to Measuring Effects
I. Standardization
II. Continuous Scale Versus Discrete Response
III. Baseline and Placebo Effect
C. Pharmacokinetic-Pharmacodynamic Models
I. Pharmacokinetics
II. Kietics of Receptor Binding
III. Steady-State Pharmacodynamic Models
IV. Non-Steady-State Pharmacodynamic Models
1. Effect Compartment
2. Physiological Mediator
V. Placebo Effect
1. Pharmacokinetics
2. Placebo Effect Model
3. Placebo Efficacy
VI. Disease Time Course and Drug Effects
1. Disease Time Course
2. Models of Drug Effect on Disease Progression
VII. Tolerance
1. Pharmacokinetics
2. Pharmacodynamics
D. Conclusion
- References
E. Future Trends in Pharmacokinetics
12 Biotechnology Products
A. Introduction
B. Pharmacokinetic/Pharmacodynamic Studies
I. Oligonucleotides
II. Proteins
1. Insulin
2. Relaxin
3. Interferon-?-2A
C. Regimen-Dependent Effects
I. Growth Hormone
II. Parathyroid Hormone
III. Tissue Plasminogen Activator
D. Binding Proteins/Inhibitors
I. Growth Hormone
II. Tissue Plasminogen Activator
III. Insulin-like Growth Factor-I
IV. Deoxyribonuclease
E. Catabolism of Biotechnology Products
I. Catabolism at Extravascular Sites of Administration
F. Drug Interactions
- References
13 Peptide and Protein Drugs
A. Introduction
I. Differences Between the Pharmacokinetics of Peptides/Proteins and Other Drugs
II. Scope of This Review
B. Pharmacokinetic Mechanisms
I. Distribution in the Body
II. Inactivation and Elimination
1. Glomerular Filtration
2. Peptidolysis
3. Receptor-Mediated Clearance
III. Uptake from Site of Administration
1. Subcutaneous or Intramuscular Injection
2. Intranasal Administration
3. Oral or Rectal Administration
IV. Pharmacokinetic Behavior Resulting from the Distribution and Elimination Processes
C. Experimental Approaches
I. Analytical Methods
1. Ex Vivo Bioassay
2. Radioimmunoassay
3. Radiolabeling
4. High-Performance Liquid Chromatography
5. Radiosequencing
II. Plasma Pharmacokinetics
1. Intravenous Bolus and Infusion Studies
2. Methods of Assaying Samples
3. Information That can Be Derived from Plasma Pharmacokinetic Studies
4. Use of Organ Ablation to Locate Clearance Sites
III. Distribution, Metabolism, and Elimination
1. Typical Experiments and Results
2. Difficulties in Interpreting Results
3. Problems in Carrying Out Drug Elimination Studies
IV. Organ Clearance
V. Receptor-Mediated Clearance Kinetics
VI. Absorption (Bioavailability) Measurement
1. Oral Route
2. Nasal Route
D. Conclusions
- References
14 Toxicokinetics
A. Introduction
B. Principles of Toxicokinetics
C. Bioanalytical Procedures to Support Toxicokinetic Studies
D. Dose-Plasma Concentration Relationship (Linear-Nonlinear Kinetics)
E. Changes in Concentrations upon Multiple Dosing
F. Designing Troubleshooting Studies to Explain Aberrant Data
I. Absorption Issues
1. Dose Proportionality
2. Effect of Diet
3. Effect of Vehicles
II. Metabolism Issues
1. Enzyme Induction
2. Effect of Age
3. Sex Dependency
G. Species Comparisons and Interspecies (Allometric) Scaling
H. Utilization of Pharmacokinetic/Toxicokinetic Data in the Design of Early Clinical Trials
- References
15 The Population Approach: Rationale, Methods, and Applications in Clinical Pharmacology and Drug Development
A. Introduction
B. Rationale
I. "Population Studies" in Large Samples of Subjects
II. Controlled Experimental Studies in Small Groups
III. The Population Approach
C. An Overview of Statistical Methodology for Model-Based Population Analysis
I. Population Model
II. Population Methods for Data Analysis
III. Synthesis
D. Current Experience with the Population Approach and Its Applications to Drug Therapy
I. Introduction
II. Detection of Patient Groups with Altered Kinetics
III. Design of Optimum A Priori Dosage Regimen
IV. Bayesian Estimation of Individual Pharmacokinetic Parameters
V. Recent Novel Applications of Nonlinear Mixed Effects Models to Other Drug-Related Areas
E. Problems and Issues?
I. Misconceptions
II. Some Practical Problems
1. Reliability of Data and Analysis
2. Methodological Issues
III. Validation of the Results
F. Integration of the Population Approach into Clinical Drug Development
I. Introduction
II. Early Human Studies (Phase I)
III. Early Clinical Studies (Phase II)
IV. Clinical Trials (Late Phase II, Phase III)
V. Late Clinical Trials (Late Phase III, Phase IV)
G. Concluding Remarks
- References
F. Impact of New Methods on Pharmacokinetics
16 Contribution of Positron Emission Tomography to Pharmacokinetic Studies
A. Introduction
B. Positron Emitters
C. Drug Labeling - Radiochemistry
D. Positron Emission Tomography
E. Direct Radiolabeled Drug Studies
I. Drug Distribution
II. Drug-Drug and Drug-Nutrient Interactions
III. Drug-Receptor Interactions
1. Tranquilizers
2. Neuroleptics
F. Indirect Radioactive Pharmacokinetic Studies
G. Kinetic Modeling with PET
I. A Two-Compartment Model: the [15O] Water Model
II. A Three-Compartment Linear Model: the [18F] Fluorodeoxyglucose Model
III. A Multicompartment Nonlinear Model: the Ligand- Receptor Model
IV. Modeling Using Simplified Models
V. Modeling Using the Multi-injection Approach
H. Conclusion
- References
17 In Vivo Imaging in Drug Discovery and Design
A. Introduction
B. Pharmacokinetics
I. Antimicrobial Agents
1. Erythromycin
2. Fluconazole
II. Antineoplastic Agents
1. Platinum Compounds
2. 5-Fluorouracil
III. Neuroleptics
IV. Angiotensin-Converting Enzyme Inhibitors
V. Nuclear Magnetic Resonance
C. Pharmacodynamics
I. Cardiovascular
1. Ventricular Function
2. Blood Volume
3. Cardiac Output
II. Renal Perfusion and Function
III. Antineoplastic Agents
IV. Liver Function
V. Intestinal Function
VI. Antimicrobial Agents
VII. Nuclear Magnetic Resonance
D. Summary
- References
G. Appendix
18 Considerations on Data Analysis Using Computer Methods and Currently Available Software for Personal Computers
A. Introduction
B. Program Features and Requirements
I. Data Entry
II. Pharmacokinetic Model Specification
1. Compartmental Models
2. Noncompartmental Approach
3. Pharmacodynamic Models
4. Absorption Kinetics and Bioavailability Studies
5. Urinary Data Analysis
6. Population Pharmacokinetics
7. Calculation of Individual Dosage Regimen
III. Error Model specification
IV. Parameter Estimation
1. Least-Squares and Maximum Likelihood Estimators
2. Linear Equations
3. Nonlinear Equations
V. Confidence Limits on Estimated Parameters
VI. Statistical Measures of Goodness of Fit
VII. Solving Systems of Differential Equations
VIII. Graphic Display of Results
IX. Printing and Plotting Results
X. User Interface and Documentation
XI. Hardware and Software Requirements
C. Directory of Surveyed Software
D. Conclusion
- References
... weniger
Bibliographische Angaben
- 2011, Softcover reprint of the original 1st ed. 1994, XXVI, 537 Seiten, Maße: 15,5 x 23,5 cm, Kartoniert (TB), Englisch
- Herausgegeben: Peter G. Welling, Luc P. Balant
- Verlag: Springer, Berlin
- ISBN-10: 3642786820
- ISBN-13: 9783642786822
Sprache:
Englisch
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