The ideal book for researchers in drug discovery who have seen their role shift from 'individual' to 'team player' where that team includes chemists, biologists, and others with strong, but varied, science backgrounds who must now work together toward their common pharmacology goal.
At GlaxoSmithKline, a pharmaceuticals world-leader, Terry Kenakin regularly teaches a course for their research scientists and has drawn on his experience to create a pharmacology primer.
*New - Latest coverage of the chemistry of drugs including expanded coverage of the pharmacokinetic discussion of druglike properties -- Increases reader understanding of necessary ADME (Absorption, Distribution, Metabolism, and Excretion) properties and increases the rate of drug approval and acceptance.
*Context - Unique discussions on various drug discovery teams and the role of the chemist on those teams -- Promotes the understanding of these expanding roles and responsibilities and how to maximize the effective contributions of each matrix team member.
*Real-world learning - There are hands-on exercises, with extensive answers, utilizing real data on structure activity relationships; utilization of pharmacological principles to make general statements about how changes in structure lead to changes in drug activity. + hands on exercises with extensive answers on Pharmacokinetics -- Stengthens practical application and understanding of core concepts and principles.
*Study sections are organized with ASPET (American Society for Pharmacology and Experimental Therapeutics)and other international organizations -- Ensures that learning follows professional industry standards.
Terry P. Kenakin is the recipient of the 2008 Poulsson Medal for Pharmacology awarded by the Norwegian Society of Pharmacology for achievements in basic and clinical pharmacology and toxicology. He has also been awarded the 2011 Ariens Award from the Dutch Pharmacological Society and the 2014 Gaddum Memorial Award from the British Pharmacological Society. Having been involved in drug discovery for over 30 years, his interests include the optimal design of drug activity assays systems and quantitative drug receptor theory. He is a member of numerous editorial boards as well as Editor-in-Chief of the Journal of Receptors and Signal Transduction and Current Opinion in Pharmacology. In addition, Dr. Kenakin has authored numerous articles and has also written a number of books on pharmacology.
This successful guide assists scientists trained in molecular biology and related fields who now need to know the basic theories, principles and practical applications of pharmacology. This latest edition continues the tradition of better preparing researchers in the basics of pharmacology. With expanded hands-on exercises and the addition of Pharmacokinetics coverage, new human interest material including historical facts in pharmacology and a new section on therapeutics that will help readers identify with diseases and drug treatments.The ideal book for researchers in drug discovery who have seen their role shift from "e;individual"e; to "e;team player"e; where that team includes chemists, biologists, and others with strong, but varied, science backgrounds who must now work together toward their common pharmacology goal. At GlaxoSmithKline, a pharmaceuticals world-leader, Terry Kenakin regularly teaches a course for their research scientists and has drawn on his experience to create a pharmacology primer.*New - Latest coverage of the chemistry of drugs including expanded coverage of the pharmacokinetic discussion of druglike properties -- Increases reader understanding of necessary ADME (Absorption, Distribution, Metabolism, and Excretion) properties and increases the rate of drug approval and acceptance. *Context - Unique discussions on various drug discovery teams and the role of the chemist on those teams -- Promotes the understanding of these expanding roles and responsibilities and how to maximize the effective contributions of each matrix team member. *Real-world learning - There are hands-on exercises, with extensive answers, utilizing real data on structure activity relationships; utilization of pharmacological principles to make general statements about how changes in structure lead to changes in drug activity. + hands on exercises with extensive answers on Pharmacokinetics -- Stengthens practical application and understanding of core concepts and principles.*Study sections are organized with ASPET (American Society for Pharmacology and Experimental Therapeutics)and other international organizations -- Ensures that learning follows professional industry standards.
Front Cover 1
A Pharmacology Primer: Theory, Applications, and Methods 4
Copyright Page 5
Dedication Page 6
Contents 10
Preface 16
Preface to the Second Edition 18
Preface to the First Edition 20
Chapter 1 : What Is Pharmacology? 22
1.1. About This Book 22
1.2. What Is Pharmacology? 22
1.3. The Receptor Concept 24
1.4. Pharmacological Test Systems 25
1.5. The Nature of Drug Receptors 27
1.6. Pharmacological Intervention and the Therapeutic Landscape 28
1.7. System-Independent Drug Parameters: Affinity and Efficacy 29
1.8. What Is Affinity? 31
1.9. The Langmuir Adsorption Isotherm 33
1.10. What Is Efficacy? 35
1.11. Dose-Response Curves 36
1.11.1. Potency and Maximal Response 37
1.11.2. p-Scales and the Representation of Potency 38
1.12. Chapter Summary and Conclusions 39
1.13. Derivations: Conformational Selection as a Mechanism of Efficacy 40
References 40
Chapter 2 : How Different Tissues Process Drug Response 42
2.1. Drug Response as seen through the "Cellular Veil" 42
2.2. The Biochemical Nature of Stimulus-Response Cascades 44
2.3. The Mathematical Approximation of Stimulus-Response Mechanisms 47
2.4. System Effects on Agonist Response: Full and Partial Agonists 47
2.5. Differential Cellular Response to Receptor Stimulus 50
2.5.1. Choice of Response Pathway 50
2.5.2. Augmentation or Modulation of Stimulus Pathway 52
2.5.3. Differences in Receptor Density 53
2.5.4. Target-Mediated Trafficking of Stimulus 53
2.6. Receptor Desensitization and Tachyphylaxis 56
2.7. The Measurement of Drug Activity 57
2.8. Advantages and Disadvantages of Different Assay Formats 57
2.9. Drug Concentration as an Independent Variable 58
2.9.1. Dissimulation in Drug Concentration 58
2.9.2. Free Concentration of Drug 59
2.10. Chapter Summary and Conclusions 60
2.11. Derivations 60
2.11.1. Series Hyperbolae Can Be Modeled by a Single Hyperbolic Function 61
2.11.2. Successive Rectangular Hyperbolic Equations Necessarily Lead to Amplification 61
2.11.3. Saturation of Any Step in a Stimulus Cascade by Two Agonists Leads to Identical Maximal Final Responses for the Two Agonists 61
2.11.4. Procedure to Measure Free Drug Concentration in the Receptor Compartment 61
References 62
Chapter 3 : Drug-Receptor Theory 64
3.1. About This Chapter 64
3.2. Drug-Receptor Theory 65
3.3. The Use of Mathematical Models in Pharmacology 66
3.4. Some Specific Uses of Models in Pharmacology 66
3.5. Classical Model of Receptor Function 68
3.6. The Operational Model of Receptor Function 69
3.7. Two-State Theory 70
3.8. The Ternary Complex Model 71
3.9. The Extended Ternary Complex Model 71
3.10. Constitutive Receptor Activity 72
3.11. The Cubic Ternary Complex Model 74
3.12. Multistate Receptor Models and Probabilistic Theory 74
3.13. Chapter Summary and Conclusions 76
3.14. Derivations 76
3.14.1. Radioligand Binding to Receptor Dimers Demonstrating Cooperative Behavior 76
3.14.2. Effect of Variation in an HIV-1 Binding Model 77
3.14.3. Derivation of the Operational Model 78
3.14.4. Operational Model Forcing Function for Variable Slope 78
3.14.5. Derivation of Two-State Theory 79
3.14.6. Derivation of the Extended Ternary Complex Model 79
3.14.7. Dependence of Constitutive Activity on Receptor Density 80
3.14.8. Derivation of the Cubic Ternary Complex Model 80
References 80
Chapter 4 : Pharmacological Assay Formats: Binding 82
4.1. The Structure of This Chapter 82
4.2. Binding Theory and Experiment 82
4.2.1. Saturation Binding 84
4.2.2. Displacement Binding 86
4.2.3. Kinetic Binding Studies 90
4.3. Complex Binding Phenomena: Agonist Affinity from Binding Curves 91
4.4. Experimental Prerequisites for Correct Application of Binding Techniques 94
4.4.1. The Effect of Protein Concentration on Binding Curves 94
4.4.2. The Importance of Equilibration Time for Equilibrium Between Two Ligands 95
4.5. Chapter Summary and Conclusions 96
4.6. Derivations 97
4.6.1. Displacement Binding: Competitive Interaction 97
4.6.2. Displacement Binding: Noncompetitive Interaction 97
4.6.3. Displacement of a Radioligand by an Allosteric Antagonist 98
4.6.4. Relationship Between IC50 and KI for Competitive Antagonists 98
4.6.5. Maximal Inhibition of Binding by an Allosteric Antagonist 98
4.6.6. Relationship Between IC50 and KI for Allosteric Antagonists 98
4.6.7. Two-Stage Binding Reactions 98
4.6.8. Effect of G-protein Coupling on Observed Agonist Affinity 99
4.6.9. Effect of Excess Receptor in Binding Experiments: Saturation Binding Curve 99
4.6.10. Effect of Excess Receptor in Binding Experiments: Displacement Experiments 99
References 99
Chapter 5 : Agonists: The Measurement of Affinity and Efficacy in Functional Assays 102
5.1. Functional Pharmacological Experiments 102
5.2. The Choice of Functional Assays 103
5.3. Recombinant Functional Systems 108
5.4. Functional Experiments: Dissimulation in Time 109
5.5. Experiments in Real Time Versus Stop Time 111
5.6. The Measurement of Agonist Affinity in Functional Experiments 112
5.6.1. Partial Agonists 112
5.6.2. Full Agonists 116
5.7. Estimates of Relative Efficacy of Agonists in Functional Experiments 117
5.8. Chapter Summary and Conclusions 118
5.9. Derivations 119
5.9.1. Relationship Between the EC50 and Affinity of Agonists 119
5.9.2. Method of Barlow, Scott, and Stephenson for Affinity of Partial Agonists 119
5.9.3. Measurement of Agonist Affinity: Method of Furchgott 120
5.9.4. Maximal Response of a Partial Agonist Is Dependent on Efficacy 120
References 121
Chapter 6 : Orthosteric Drug Antagonism 122
6.1. Introduction 122
6.2. Kinetics of Drug-Receptor Interaction 123
6.3. Surmountable Competitive Antagonism 125
6.3.1. Schild Analysis 125
6.3.2. Patterns of Dose-Response Curves That Preclude Schild Analysis 129
6.3.3. Best Practice for the Use of Schild Analysis 130
6.3.4. Analyses for Inverse Agonists in Constitutively Active Receptor Systems 131
6.3.5. Analyses for Partial Agonists 134
6.3.6. The Method of Lew and Angus: Nonlinear Regressional Analysis 135
6.4. Noncompetitive Antagonism 137
6.5. Agonist-Antagonist Hemi-Equilibria 140
6.6. Resultant Analysis 142
6.7. Chapter Summary and Conclusions 142
6.8. Derivations 143
6.8.1. Derivation of the Gaddum Equation for Competitive Antagonism 144
6.8.2. Derivation of the Gaddum Equation for Noncompetitive Antagonism 144
6.8.3. Derivation of the Schild Equation 144
6.8.4. Functional Effects of an Inverse Agonist with the Operational Model 145
6.8.5. pA2 Measurement for Inverse Agonists 145
6.8.6. Functional Effects of a Partial Agonist with the Operational Model 145
6.8.7. pA2 Measurements for Partial Agonists 146
6.8.8. Method of Stephenson for Partial Agonist Affinity Measurement 146
6.8.9. Derivation of the Method of Gaddum for Noncompetitive Antagonism 146
6.8.10. Relationship of pA2 and pKB for Insurmountable Orthosteric Antagonism 147
6.8.11. Resultant Analysis 147
References 148
Chapter 7 : Allosteric Drug Antagonism 150
7.1. Introduction 150
7.2. The Nature of Receptor Allosterism 150
7.3. Properties of Allosteric Modulators 152
7.4. Functional Study of Allosteric Modulators 157
7.4.1. Surmountable Allosteric Modulation (epsiv = 1) 158
7.4.2. Insurmountable Allosteric Antagonism (epsiv = 0) 159
7.4.3. Variable Effects on Efficacy (epsiv 0) 160
7.5. Measurement of the Potency of Allosteric Insurmountable Antagonists 161
7.6. Methods for Detecting Allosterism 163
7.7. Chapter Summary and Conclusions 165
7.8. Derivations 165
7.8.1. Allosteric Model of Receptor Activity 165
7.8.2. Effects of Allosteric Ligands on Response: Changing Efficacy 166
7.8.3. Schild Analysis for Allosteric Antagonists 166
7.8.4. Relationship of pA2 and pKB for Insurmountable Allosteric Antagonism 167
References 167
Chapter 8 : The Process of Drug Discovery 170
8.1. Pharmacology in Drug Discovery 170
8.2. Chemical Sources for Potential Drugs 170
8.3. Pharmacodynamics and High-Throughput Screening 176
8.4. Drug Discovery and Development 184
8.4.1. Safety Pharmacology 189
8.5. Clinical Testing 196
8.6. Chapter Summary and Conclusions 197
References 197
Chapter 9 : Pharmacokinetics 200
9.1. Introduction 200
9.2. Biopharmaceutics 200
9.3. The Chemistry of "Druglike" Character 201
9.4. Pharmacokinetics 205
9.4.1. Drug Absorption 205
9.4.2. Route of Drug Administration 209
9.4.3. General Pharmacokinetics 212
9.4.4. Metabolism 214
9.4.5. Clearance 215
9.4.6. Volume of Distribution and Half Life 217
9.4.7. Renal Clearance 223
9.4.8. Bioavailability 225
9.5. NonLinear Pharmacokinetics 226
9.6. Multiple Dosing 227
9.7. Practical Pharmacokinetics 230
9.7.1. Allometric Scaling 230
9.8. Placement of Pharmacokinetic Assays in Discovery and Development 232
9.9. Summary and Conclusions 235
References 235
Chapter 10 : Target- and System-Based Strategies for Drug Discovery 236
10.1. Some Challenges for Modern Drug Discovery 236
10.2. Target-Based Drug Discovery 237
10.2.1. Target Validation and the Use of Chemical Tools 238
10.2.2. Recombinant Systems 241
10.2.3. Defining Biological Targets 242
10.3. Systems-Based Drug Discovery 245
10.3.1. Assays in Context 249
10.4. In Vivo Systems, Biomarkers, and Clinical Feedback 250
10.5. Types of Therapeutically Active Ligands: Polypharmacology 252
10.6. Summary and Conclusions 256
References 257
Chapter 11 : "Hit" to Drug: Lead Optimization 260
11.1. Tracking SAR and Determining Mechanism of Action: Data Driven Drug-Based PharmacoLogy 260
11.2. Drug Initiation of Response: Agonism 261
11.2.1. Analysis of Full Agonism 262
11.2.2. Quantifying Full Agonist Potency Ratios 264
11.2.3. Analysis of Partial Agonism 264
11.2.4. Fitting Data to the Operational Model 265
11.2.5. Affinity-Dependent versus Efficacy-Dependent Agonist Potency 267
11.2.6. Secondary and Tertiary Testing of Agonists 270
11.3. Inhibition of Agonist Response: Antagonism 271
11.3.1. Initial Antagonist Potency: pIC50 Curves 271
11.3.2. Secondary Testing of Antagonists 276
11.3.3. Determining Mode of Antagonist Action 278
11.3.4. Use of the pA2 as a Universal Determinant of Antagonist Potency 279
11.3.5. Logistics of Analysis of Antagonism 280
11.4. Summary and Conclusions 286
11.5. Derivations 286
11.5.1. System Independence of Full Agonist Potency Ratios: Classical and Operational Models 289
11.5.2. Model for Allosteric Agonism 289
11.5.3. IC50 Correction Factors: Competitive Antagonists 290
11.5.4. Relationship of pA2 and pKB for Insurmountable Orthosteric Antagonism 290
11.5.5. Relationship of pA2 and pKB for Insurmountable Allosteric Antagonism 291
11.5.6. Operational Model for Partial Agonist Interaction with Agonist: Variable Slope 291
11.5.7. Operational Model for Inverse Agonist Interaction with Agonist: Variable Slope 291
11.5.8. Surmountable Allosteric Antagonism: Variable Slope 292
11.5.9. Functional Model for Hemi-Equilibrium Effects: Variable Slope 292
11.5.10. Allosteric Antagonism with Changes in Efficacy: Variable Slope 292
11.5.11. Orthosteric Insurmountable Antagonism: Operational Model with Variable Slope 292
11.5.12. Allosteric Insurmountable Antagonism: Operational Model with Variable Slope 293
References 293
Chapter 12 : Statistics and Experimental Design 294
12.1. Structure of This Chapter 294
12.2. Introduction 294
12.3. Descriptive Statistics: Comparing Sample Data 294
12.3.1. Gaussian Distribution 295
12.3.2. Populations and Samples 295
12.3.3. Confidence Intervals 297
12.3.4. Paired Data Sets 298
12.3.5. One-Way Analysis of Variance 299
12.3.6. Two-Way Analysis of Variance 300
12.3.7. Regression and Correlation 300
12.3.8. Detection of Single versus Multiple Populations 302
12.4. How Consistent Is Experimental Data with Models? 303
12.4.1. Comparison of Data to Models: Choice of Model 303
12.4.2. Curve Fitting: Good Practice 306
12.4.3. Outliers and Weighting Data Points 306
12.4.4. Overextrapolation of Data 308
12.4.5. Hypothesis Testing: Examples with Dose-Response Curves 310
12.4.6. One Curve or Two? Detection of Differences in Curves 312
12.4.7. Asymmetrical Dose-Response Curves 313
12.4.8. Comparison of Data to Linear Models 314
12.4.9. Is a Given Regression Linear? 315
12.4.10. One or More Regression Lines? Analysis of Covariance 316
12.5. Comparison of Samples to "Standard Values" 318
12.5.1. Comparison of Means by Two Methods or in Two Systems 319
12.5.2. Comparing Assays/Methods with a Range of Ligands 319
12.6. Experimental Design and Quality Control 320
12.6.1. Detection of Difference in Samples 320
12.6.2. Power Analysis 321
12.7. Chapter Summary and Conclusions 322
References 323
Chapter 13 : Selected Pharmacological Methods 324
13.1. Binding Experiments 324
13.1.1. Saturation Binding 324
13.1.2. Displacement Binding 324
13.2. Functional Assays 326
13.2.1. Determination of Equiactive Concentrations on Dose-Response Curves 326
13.2.2. Method of Barlow, Scott, and Stephenson for Measurement of the Affinity of a Partial Agonist 328
13.2.3. Method of Furchgott for the Measurement of the Affinity of a Full Agonist 329
13.2.4. Schild Analysis for the Measurement of Competitive Antagonist Affinity 331
13.2.5. Method of Stephenson for Measurement of Partial Agonist Affinity 333
13.2.6. Method of Gaddum for Measurement of Noncompetitive Antagonist Affinity 334
13.2.7. Method for Estimating Affinity of Insurmountable Antagonist (Dextral Displacement Observed) 336
13.2.8. Resultant Analysis for Measurement of Affinity of Competitive Antagonists with Multiple Properties 337
13.2.9. Measurement of the Affinity and Maximal Allosteric Constant for Allosteric Modulators Producing Surmountable Effects 338
13.2.10. Method for Estimating Affinity of Insurmountable Antagonist (No Dextral Displacement Observed): Detection of Allosteric Effect 339
13.2.11. Measurement of pKB for Competitive Antagonists from a pIC50 341
13.2.12. Kinetics of Antagonist Offset 343
Chapter 14 : Exercises in Pharmacodynamics and Pharmacokinetics 348
14.1. Introduction 348
14.2. Agonism 348
14.2.1. Agonism: Structure-Activity Relationships 348
14.2.2. Prediction of Agonist Effect 350
14.2.3. "Super Agonists" 350
14.2.4. Atypical Agonists 351
14.2.5. Ordering of Affinity and Efficacy in Agonist Series 351
14.2.6. Kinetics of Agonism 351
14.2.7. Affinity-Dominant Versus Efficacy-Dominant Agonists 352
14.2.8. Agonist Affinities and Potencies Do Not Correlate 355
14.2.9. Lack of Agonist Effect 356
14.2.10. Assay-Specific Agonism 357
14.3. Antagonism 358
14.3.1. Antagonist Potency and Kinetics: Part A 358
14.3.2. Antagonist Potency in pIC50 Format (Kinetics Part B) 360
14.3.3. Mechanism of Antagonist Action (Kinetics Part C) 361
14.3.4. Mechanism of Antagonist Action: Curve Patterns 362
14.3.5. Mechanism of Action: Incomplete Antagonism 362
14.3.6. pIC50 Mode: Antagonism Below Basal 364
14.3.7. Secondary Effects of Antagonists 365
14.3.8. Antagonist Potency Variably Dependent on Agonist Concentration 365
14.4. In Vitro-In Vivo Transitions and General Discovery 367
14.4.1. "Silent Antagonism" 367
14.4.2. Loss of Activity 368
14.4.3. Marking Relevant Agonism 369
14.4.4. In Vitro-In Vivo Correspondence of Activity 369
14.4.5. Divergent Agonist-Dependent Antagonism 370
14.5. SAR Exercises 372
14.5.1. Surrogate Screens 372
14.6. Pharmacokinetics 372
14.6.1. Clearance 372
14.6.2. Drug-Drug Interactions 373
14.6.3. Distribution I 373
14.6.4. Distribution II 373
14.6.5. Half Life I 374
14.6.6. Half Life II 374
14.6.7. Half Life III 375
14.6.8. Renal Clearance I 375
14.6.9. Renal Clearance II 375
14.6.10. Renal Clearance III 375
14.6.11. Absorption 375
14.6.12. Predictive Pharmacokinetics I 375
14.6.13. Predictive Pharmacokinetics II 376
14.6.14. Predictive Pharmacokinetics III 376
14.6.15. Log D and Pharmacokinetics 376
14.7. Conclusions 376
References 376
Appendices 378
A.1. Statistical Tables of Use for Assessing Significant Difference 378
A.1.1. t-Distribution 378
A.1.2. F-Distribution 379
A.2. Mathematical Fitting Functions 386
Glossary of Pharmacological Terms 392
Index 400
| Erscheint lt. Verlag | 7.2.2009 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizin / Pharmazie ► Gesundheitsfachberufe | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie | |
| Naturwissenschaften ► Biologie | |
| Technik | |
| ISBN-10 | 0-08-092333-X / 008092333X |
| ISBN-13 | 978-0-08-092333-8 / 9780080923338 |
| Haben Sie eine Frage zum Produkt? |
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