Basic Pharmacokinetics and Pharmacodynamics (eBook)
John Wiley & Sons (Verlag)
978-1-119-14316-1 (ISBN)
• Presents the essentials of pharmacokinetics and pharmacodynamics in a clear and progressive manner
• Helps students better appreciate important concepts and gain a greater understanding of the mechanism of action of drugs by reinforcing practical applications in both the book and the computer modules
• Features interactive computer simulations, available online through a companion website at: https://web.uri.edu/pharmacy/research/rosenbaum/sims/
• Adds new chapters on physiologically based pharmacokinetic models, predicting drug-drug interactions, and pharmacogenetics while also strengthening original chapters to better prepare students for more advanced applications
• Reviews of the 1st edition: 'This is an ideal textbook for those starting out ... and also for use as a reference book ....' (International Society for the Study of Xenobiotics) and 'I could recommend Rosenbaum's book for pharmacology students because it is written from a perspective of drug action . . . Overall, this is a well-written introduction to PK/PD .... ' (British Toxicology Society Newsletter)
Sara E. Rosenbaum, PhD, is Professor of Biomedical and Pharmaceutical Sciences at the University of Rhode Island, where she teaches courses in pharmacokinetics and pharmacodynamics. Her research interests concentrate on the development and application of pharmacokinetic and pharmacodynamic models to better understand the drug dose-response relationship.
Updated with new chapters and topics, this book provides a comprehensive description of all essential topics in contemporary pharmacokinetics and pharmacodynamics. It also features interactive computer simulations for students to experiment and observe PK/PD models in action. Presents the essentials of pharmacokinetics and pharmacodynamics in a clear and progressive manner Helps students better appreciate important concepts and gain a greater understanding of the mechanism of action of drugs by reinforcing practical applications in both the book and the computer modules Features interactive computer simulations, available online through a companion website at: https://web.uri.edu/pharmacy/research/rosenbaum/sims/ Adds new chapters on physiologically based pharmacokinetic models, predicting drug-drug interactions, and pharmacogenetics while also strengthening original chapters to better prepare students for more advanced applications Reviews of the 1st edition: This is an ideal textbook for those starting out and also for use as a reference book ."e; (International Society for the Study of Xenobiotics) and I could recommend Rosenbaum s book for pharmacology students because it is written from a perspective of drug action . . . Overall, this is a well-written introduction to PK/PD . (British Toxicology Society Newsletter)
Sara E. Rosenbaum, PhD, is Professor of Biomedical and Pharmaceutical Sciences at the University of Rhode Island, where she teaches courses in pharmacokinetics and pharmacodynamics. Her research interests concentrate on the development and application of pharmacokinetic and pharmacodynamic models to better understand the drug dose-response relationship.
Basic Pharmacokinetics and Pharmacodynamics 3
Contents 9
Preface 21
Contributors 23
1 Introduction to Pharmacokinetics and Pharmacodynamics 27
1.1 Introduction: Drugs and Doses 28
1.2 Introduction to Pharmacodynamics 29
1.2.1 Drug Effects at the Site of Action 29
1.2.2 Agonists, Antagonists, and Concentration–Response Relationships 32
1.3 Introduction to Pharmacokinetics 35
1.3.1 Plasma Concentration of Drugs 35
1.3.2 Processes in Pharmacokinetics 37
1.4 Dose–Response Relationships 38
1.5 Therapeutic Range 40
1.5.1 Determination of the Therapeutic Range 41
1.6 Summary 44
Reference 44
2 Passage of Drugs Through Membranes 45
2.1 Introduction 46
2.2 Structure and Properties of Membranes 46
2.3 Passive Diffusion 47
2.3.1 Transcellular Passive Diffusion 49
2.3.2 Paracellular Passive Diffusion 51
2.4 Carrier-Mediated Processes: Transport Proteins 52
2.4.1 Uptake Transporters: SLC Superfamily 53
2.4.2 Efflux Transporters: ABC Superfamily 55
2.4.3 Characteristics of Transporter Systems 57
2.4.4 Simulation Exercise: http:web.uri.edupharmacyresearchrosenbaumsims 58
2.4.5 Clinical Examples of Transporter Involvement in Drug Response 58
References 59
3 Drug Administration and Drug Absorption 61
3.1 Introduction: Local and Systemic Drug Administration 62
3.2 Routes of Drug Administration 63
3.2.1 Common Routes of Local Drug Administration 63
3.2.2 Common Routes of Systemic Drug Administration 64
3.3 Overview of Oral Absorption 67
3.3.1 Anatomy and Physiology of the Oral-Gastric-Intestinal Tract and Transit Time 67
3.4 Extent of Drug Absorption 70
3.4.1 Bioavailability Factor 70
3.4.2 Individual Bioavailability Factors 71
3.5 Determinants of the Fraction of the Dose Absorbed (F) 72
3.5.1 Disintegration 72
3.5.2 Dissolution 72
3.5.3 Formulation Excipients 76
3.5.4 Adverse Events within the Gastrointestinal Lumen 76
3.5.5 Transcellular Passive Diffusion 79
3.5.6 Particulate Uptake 79
3.5.7 Paracellular Passive Diffusion 79
3.5.8 Uptake and Efflux Transporters 80
3.5.9 Presystemic Intestinal Metabolism or Extraction 84
3.5.10 Presystemic Hepatic Metabolism or Extraction 86
3.6 Factors Controlling the Rate of Drug Absorption 87
3.6.1 Dissolution-Controlled Absorption 89
3.6.2 Membrane Penetration-Controlled Absorption 89
3.6.3 Overall Rate of Drug Absorption 89
3.7 Biopharmaceutics Classification System 90
3.7.1 Intestinal Reserve Length 90
3.7.2 Biopharmaceutics Classification System (BCS) 90
3.7.3 Biopharmaceutics Drug Disposition Classification System (BDDCS) 91
3.8 Food Effects 91
References 93
4 Drug Distribution 97
4.1 Introduction 98
4.2 Extent of Drug Distribution 98
4.2.1 Distribution Volumes 100
4.2.2 Tissue Binding, Plasma Protein Binding, and Partitioning: Concentrating Effects 101
4.2.3 Assessment of the Extent of Drug Distribution: Apparent Volume of Distribution 102
4.2.4 Plasma Protein Binding 108
4.3 Rate of Drug Distribution 115
4.3.1 Perfusion-Controlled Drug Distribution 116
4.3.2 Diffusion or Permeability-Controlled Drug Distribution 119
4.4 Distribution of Drugs to the Central Nervous System 119
References 124
5 Drug Elimination and Clearance 125
5.1 Introduction 126
5.1.1 First-Order Elimination 127
5.1.2 Determinants of the Elimination Rate Constant and the Half-Life 128
5.2 Clearance 128
5.2.1 Definition and Determinants of Clearance 128
5.2.2 Total Clearance, Renal Clearance, and Hepatic Clearance 130
5.2.3 Relationships among Clearance, Volume of Distribution, Elimination Rate Constant, and Half-Life 131
5.2.4 Primary and Secondary Parameters 132
5.2.5 Measurement of Total Body Clearance 132
5.3 Renal Clearance 134
5.3.1 Glomerular Filtration 135
5.3.2 Tubular Secretion 136
5.3.3 Tubular Reabsorption 139
5.3.4 Putting Meaning into the Value of Renal Clearance 140
5.3.5 Measurement of Renal Clearance 141
5.3.6 Fraction of the Dose Excreted Unchanged 144
5.4 Hepatic Elimination and Clearance 145
5.4.1 Phase I and Phase II Metabolism 146
5.4.2 The Cytochrome P450 Enzyme System 147
5.4.3 Glucuronidation 148
5.4.4 Metabolism-Based Drug–Drug Interactions 148
5.4.5 Hepatic Drug Transporters and Drug–Drug Interactions 151
5.4.6 Kinetics of Drug Metabolism 153
5.4.7 Hepatic Clearance and Related Parameters 154
References 168
6 Compartmental Models in Pharmacokinetics 171
6.1 Introduction 172
6.2 Expressions for Component Parts of the Dose–Plasma Concentration Relationship 172
6.2.1 Effective Dose 172
6.2.2 Rate of Drug Absorption 173
6.2.3 Rate of Drug Elimination 174
6.2.4 Rate of Drug Distribution 174
6.3 Putting Everything Together: Compartments and Models 175
6.3.1 One-Compartment Model 175
6.3.2 Two-Compartment Model 176
6.3.3 Three-Compartment Model 176
6.4 Examples of Complete Compartment Models 178
6.4.1 Intravenous Bolus Injection in a One-Compartment Model with First-Order Elimination 178
6.4.2 Intravenous Bolus Injection in a Two-Compartment Model with First-Order Elimination 179
6.4.3 First-Order Absorption in a Two-Compartment Model with First-Order Elimination 180
6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics 181
6.6 Selecting and Applying Models 182
Suggested Readings 183
7 Pharmacokinetics of an Intravenous Bolus Injection in a One-Compartment Model 185
7.1 Introduction 186
7.2 One-Compartment Model 186
7.3 Pharmacokinetic Equations 188
7.3.1 Basic Equation 188
7.3.2 Half-Life 189
7.3.3 Time to Eliminate a Dose 189
7.4 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 189
7.5 Application of the Model 191
7.5.1 Predicting Plasma Concentrations 191
7.5.2 Duration of Action 192
7.5.3 Value of a Dose to Give a Desired Initial Plasma Concentration 193
7.5.4 Intravenous Loading Dose 193
7.6 Determination of Pharmacokinetic Parameters Experimentally 194
7.6.1 Study Design for the Determination of Parameters 194
7.6.2 Pharmacokinetic Analysis 195
7.7 Pharmacokinetic Analysis in Clinical Practice 199
Suggested Reading 202
8 Pharmacokinetics of an Intravenous Bolus Injection In A Two-Compartment Model 203
8.1 Introduction 204
8.2 Tissue and Compartmental Distribution of a Drug 205
8.2.1 Drug Distribution to the Tissues 205
8.2.2 Compartmental Distribution of a Drug 206
8.3 Basic Equation 207
8.3.1 Distribution: A, a, and the Distribution t12 208
8.3.2 Elimination: B, b, and the b t12 208
8.4 Relationship Between Macro and Micro Rate Constants 209
8.5 Primary Pharmacokinetic Parameters 209
8.5.1 Clearance 210
8.5.2 Distribution Clearance 210
8.5.3 Volume of Distribution 212
8.6 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 214
8.7 Determination of the Pharmacokinetic Parameters of the Two-Compartment Model 217
8.7.1 Determination of Intercepts and Macro Rate Constants 217
8.7.2 Determination of the Micro Rate Constants: k12, k21, and k10 219
8.7.3 Determination of the Primary Pharmacokinetic Parameters 219
8.8 Clinical Application of the Two-Compartment Model 220
8.8.1 Measurement of the Elimination Half-Life in the Postdistribution Phase 220
8.8.2 Determination of the Loading Dose 221
8.8.3 Evaluation of a Dose: Monitoring Plasma Concentrations and Patient Response 223
Suggested Readings 225
9 Pharmacokinetics of Extravascular Drug Administration 227
9.1 Introduction 228
9.2 First-Order Absorption in a One-Compartment Model 229
9.2.1 Model and Equations 229
9.2.2 Parameter Determination 231
9.2.3 Absorption Lag Time 236
9.2.4 Flip-Flop Model and Sustained-Release Preparations 238
9.2.5 Determinants of Tmax and Cmax 238
9.3 Modified Release and Gastric Retention Formulations 240
9.3.1 Impact of the Stomach 240
9.3.2 Moisture in the Gastrointestinal Tract 241
9.4 Bioavailability 241
9.4.1 Bioavailability Parameters 241
9.4.2 Absolute Bioavailability 243
9.4.3 Relative Bioavailability 243
9.4.4 Bioequivalence 243
9.4.5 Single-Dose Crossover Parallel and Steady-State Study Designs 245
9.4.6 Example Bioavailability Analysis 245
9.5 IN VITRO-IN VIVO Correlation 245
9.5.1 Definitions 245
9.5.2 Assumptions 246
9.5.3 Utility 246
9.5.4 Immediate Release IVIVC 246
9.5.5 Modified Release IVIVC 247
9.6 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 248
References 250
10 Introduction to Noncompartmental Analysis 251
10.1 Introduction 251
10.2 Mean Residence Time 252
10.3 Determination of Other Important Pharmacokinetic Parameters 255
10.4 Different Routes of Administration 257
10.5 Application of Noncompartmental Analysis to Clinical Studies 258
11 Pharmacokinetics of Intravenous Infusion in a One-Compartment Model 263
11.1 Introduction 264
11.2 Model and Equations 265
11.2.1 Basic Equation 265
11.2.2 Application of the Basic Equation 267
11.2.3 Simulation Exercise: Part 1: http://web.uri.edu/pharmacy/research/rosenbaum/sims 267
11.3 Steady-State Plasma Concentration 268
11.3.1 Equation for Steady-State Plasma Concentrations 268
11.3.2 Application of the Equation 268
11.3.3 Basic Formula Revisited 269
11.3.4 Factors Controlling Steady-State Plasma Concentration 269
11.3.5 Time to Steady State 270
11.3.6 Simulation Exercise: Part 2: http://web.uri.edu/pharmacy/research/rosenbaum/sims 271
11.4 Loading Dose 272
11.4.1 Loading-Dose Equation 272
11.4.2 Simulation Exercise: Part 3 274
11.5 Termination of Infusion 274
11.5.1 Equations for Termination Before and After Steady State 274
11.5.2 Simulation Exercise: Part 4 275
11.6 Individualization of Dosing Regimens 275
11.6.1 Initial Doses 275
11.6.2 Monitoring and Individualizing Therapy 276
12 Multiple Intravenous Bolus Injections in the One-Compartment Model 281
12.1 Introduction 282
12.2 Terms and Symbols Used in Multiple-Dosing Equations 283
12.3 Monoexponential Decay During a Dosing Interval 285
12.3.1 Calculation of Dosing Interval to Give Specific Steady-State Peaks and Troughs 286
12.4 Basic Pharmacokinetic Equations for Multiple Doses 286
12.4.1 Principle of Superposition 286
12.4.2 Equations that Apply Before Steady State 287
12.5 Steady State 288
12.5.1 Steady-State Equations 289
12.5.2 Average Plasma Concentration at Steady State 290
12.5.3 Fluctuation 293
12.5.4 Accumulation 293
12.5.5 Time to Reach Steady State 295
12.5.6 Loading Dose 296
12.6 Basic Formula Revisited 296
12.7 Pharmacokinetic-Guided Dosing Regimen Design 296
12.7.1 General Considerations for Selection of the Dosing Interval 296
12.7.2 Protocols for Pharmacokinetic-Guided Dosing Regimens 298
12.8 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 302
Reference 304
13 Multiple Intermittent Infusions 305
13.1 Introduction 305
13.2 Steady-State Equations for Multiple Intermittent Infusions 307
13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks, Troughs, and Elimination Half-Life 310
13.3.1 Determination of Half-Life 310
13.3.2 Determination of Peaks and Troughs 312
13.4 Determination of the Volume of Distribution 312
13.5 Individualization of Dosing Regimens 315
13.6 Simulation: http://web.uri.edu/pharmacy/research/rosenbaum/sims 315
14 Multiple Oral Doses 319
14.1 Introduction 319
14.2 Steady-State Equations 320
14.2.1 Time to Peak Steady-State Plasma Concentration 321
14.2.2 Maximum Steady-State Plasma Concentration 322
14.2.3 Minimum Steady-State Plasma Concentration 322
14.2.4 Average Steady-State Plasma Concentration 322
14.2.5 Overall Effect of Absorption Parameters on a Steady-State Dosing Interval 323
14.3 Equations Used Clinically to Individualize Oral Doses 324
14.3.1 Protocol to Select an Appropriate Equation 324
14.4 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 326
References 327
15 Nonlinear Pharmacokinetics 329
15.1 Linear Pharmacokinetics 330
15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination 332
15.3 Pharmacokinetics of Capacity-Limited Metabolism 333
15.3.1 Kinetics of Enzymatic Processes 333
15.3.2 Plasma Concentration–Time Profile 335
15.4 Phenytoin 336
15.4.1 Basic Equation for Steady State 337
15.4.2 Estimation of Doses and Plasma Concentrations 339
15.4.3 Influence of Km and Vmax and Factors That Affect These Parameters 340
15.4.4 Time to Eliminate the Drug 342
15.4.5 Time to Reach Steady State 343
15.4.6 Individualization of Doses of Phenytoin 344
References 348
16 Introduction to Pharmacogenetics 349
16.1 Introduction 350
16.2 Genetics Primer 350
16.2.1 Basic Terminology: Genes, Alleles, Loci, and Polymorphism 350
16.2.2 Population Genetics: Allele and Genotype Frequencies 352
16.2.3 Quantitative Genetics and Complex Traits 353
16.3 Pharmacogenetics 354
16.3.1 Pharmacogenetics of Drug-Metabolizing Enzymes 356
16.3.2 Pharmacogenetics of Drug Transporters 359
16.4 Genetics and Pharmacodynamics 360
16.4.1 Drug Target Pharmacogenetics 360
16.5 Summary 361
Reference 361
Suggested Readings 361
17 Models Used to Predict Drug–Drug Interactions for Orally Administered Drugs 363
17.1 Introduction 364
17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism Based on IN VITRO Data 366
17.2.1 Reversible Inhibition 366
17.2.2 Time-Dependent Inhibition 367
17.2.3 Induction 371
17.3 Surrogate IN VIVO Values for the Unbound Concentration of the Perpetrator at the site of action 371
17.3.1 Surrogate Measures of Hepatic Inhibitor and Inducer Concentrations 372
17.3.2 Surrogate Measures of Intestinal Inhibitor and Inducer Concentrations 372
17.4 Models Used to Predict DDIs IN VIVO 373
17.4.1 Introduction 373
17.4.2 Basic Predictive Models: R Values 374
17.4.3 Predictive Models Incorporating Parallel Pathways of Elimination (fm) 376
17.4.4 Models Incorporating Intestinal Extraction 380
17.4.5 Models Combining Multiple Actions of Perpetrators 384
17.5 Predictive Models for Transporter-Based DDIs 385
17.5.1 Kinetics of Drug Transporters 385
17.6 Application of Physiologically Based Pharmacokinetic Models to DDI Prediction: The Dynamic Approach 388
17.7 Conclusion 388
References 390
18 Introduction to Physiologically Based Pharmacokinetic Modeling 393
18.1 Introduction 394
18.2 Components of PBPK Models 395
18.3 Equations for PBPK Models 395
18.4 Building a PBPK Model 399
18.5 Simulations: http://web.uri.edu/pharmacy/research/rosenbaum/sims 403
18.6 Estimation of Human Drug-Specific Parameters 404
18.6.1 Tissue Plasma Partition Coefficient 405
18.6.2 Volume of Distribution 405
18.6.3 Clearance 406
18.7 More Detailed PBPK Models 407
18.7.1 Permeability-Limited Distribution 407
18.7.2 Drug Transporters 409
18.7.3 Models for Oral Absorption 412
18.7.4 Reduced Models 413
18.8 Application of PBPK Models 413
References 414
19 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic–Pharmacodynamic Models 417
19.1 Introduction 418
19.2 Classic Pharmacodynamic Models Based on Receptor Theory 419
19.2.1 Receptor Binding 420
19.2.2 Concentration-Response Models 421
19.3 Direct Effect Pharmacodynamic Models 428
19.3.1 Emax and Sigmoidal Emax Models 428
19.3.2 Inhibitory Imax and Sigmoidal Imax Models 430
19.3.3 Linear Adaptations of the Emax and Imax Model 430
19.4 Integrated PK–PD Models: Intravenous Bolus Injection in the One-Compartment Mode and the Sigmoidal Emax Model 432
19.4.1 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 435
19.5 Pharmacodynamic Drug–Drug Interactions 436
19.5.1 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 436
References 438
20 Semimechanistic Pharmacokinetic–Pharmacodynamic Models 439
20.1 Introduction 440
20.2 Hysteresis and the Effect Compartment 442
20.2.1 Simulation Exercise: http://web.uri.edu/pharmacy/research/rosenbaum/sims 445
20.3 Physiological Turnover Models and Their Characteristics 445
20.3.1 Points of Drug Action 447
20.3.2 System Recovery After Change in Baseline Value 447
20.4 Indirect Effect Models 448
20.4.1 Introduction 448
20.4.2 Characteristics of Indirect Effect Drug Responses 450
20.4.3 Characteristics of Indirect Effect Models Illustrated Using Model I 452
20.5 Other Indirect Effect Models 458
20.5.1 Transit Compartment Models 461
20.5.2 Model for Hematological Toxicity of Anticancer Drugs 465
20.5.3 Alternate Parameterizations of Transit Models 468
20.6 Models of Tolerance 468
20.6.1 Introduction to Pharmacologic Tolerance 468
20.6.2 Counter-Regulatory Force Tolerance Model 470
20.6.3 Precursor Pool Model of Tolerance 473
20.7 Irreversible Drug Effects 476
20.7.1 Application of the Turnover Model to Irreversible Drug Action 476
20.8 Disease Progression Models 478
20.8.1 Drug Pharmacokinetics 478
20.8.2 Pharmacodynamics 478
20.8.3 Disease Activity Models 479
20.8.4 Disease Progression Models 479
References 491
Appendix A Review of Exponents and Logarithms 495
A.1 Exponents 495
A.2 Logarithms: Log and Ln 496
A.3 Performing Calculations in the Logarithmic Domain 497
A.3.1 Multiplication 497
A.3.2 Division 498
A.3.3 Reciprocals 498
A.3.4 Exponents 498
A.4 Calculations Using Exponential Expressions and Logarithms 498
A.5 Decay Function: e?kt 500
A.6 Growth Function: 1 ? e?kt 501
A.7 Decay Function in Pharmacokinetics 501
Appendix B Rates of Processes 505
B.1 Introduction 505
B.2 Order of a Rate Process 506
B.3 Zero-Order Processes 506
B.3.1 Equation for Zero-Order Filling 506
B.3.2 Equation for Zero-Order Emptying 507
B.3.3 Time for Zero-Order Emptying to Go to 50% Completion 507
B.4 First-Order Processes 508
B.4.1 Equation for a First-Order Process 508
B.4.2 Time for 50% Completion: the Half-Life 509
B.5 Comparison of Zero- and First-Order Processes 510
B.6 Detailed Example of First-Order Decay in Pharmacokinetics 510
B.6.1 Equations and Semilogarithmic Plots 510
B.6.2 Half-Life 511
B.6.3 Fraction or Percent Completion of a First-Order Process Using First-Order Elimination as an Example 511
B.7 Examples of the Application of First-Order Kinetics to Pharmacokinetics 513
Appendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 515
C.1 Measurement of AUC and Clearance 515
C.1.1 Trapezoidal Rule 516
C.1.2 Excel Spreadsheet to Determine AUC0 and Clearance 517
C.2 Analysis of Data from an Intravenous Bolus Injection in a One-Compartment Model 520
C.3 Analysis of Data from an Intravenous Bolus Injection in a Two-Compartment Model 522
C.4 Analysis of Oral Data in a One-Compartment Model 524
C.5 Noncompartmental Analysis of Oral Data 527
Appendix D Derivation of Equations for Multiple Intravenous Bolus Injections 531
D.1 Assumptions 531
D.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections 531
D.3 Steady-State Equations 534
Appendix E Enzyme Kinetics: Michaelis–Menten Equation and Models for Inhibitors and Inducers of Drug Metabolism 535
E.1 Kinetics of Drug Metabolism: The Michaelis–Menten Model 536
E.1.1 Overview 536
E.1.2 Assumptions for Validity of Michaelis–Menten Model 536
E.1.3 Km and Vmax 537
E.1.4 Derivation of the Michaelis–Menten Equation 537
E.1.5 Summary, Practical Considerations, and Interpretations 539
E.1.6 Relationship Between Intrinsic Clearance and the Michaelis–Menten Parameters 540
E.2 Effect of Perpetrators of DDI on Enzyme Kinetics and Intrinsic Clearance 541
E.2.1 Reversible Inhibition 541
E.2.2 Time-Dependent Inhibition 544
E.2.3 Enzyme Induction 550
References 552
Appendix F Summary of the Properties of the Fictitious Drugs used in the Text 553
Appendix G Computer Simulation Models 555
Glossary of Terms 557
Index 563
Supplemental Images 579
EULA 589
| Erscheint lt. Verlag | 22.11.2016 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie |
| Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
| Naturwissenschaften ► Chemie | |
| Schlagworte | ADME • Bioavailability • Biopharmaceutics • Chemie • Chemistry • Clinical Pharmacology & Therapeutics • drug action mechanisms • drug administration • drug disintegration • Drug dissolution • Drug-drug Interactions • Klinische Pharmakologie u. Therapie • <p>PKPD • Medical Science • Medizin • Molecular Pharmacology • Molekulare Pharmakologie • non-compartmental analysis</p> • Pharmaceutical Statistics • Pharmacodynamics • Pharmacogenetics • Pharmacokinetics • Pharmakodynamik • Pharmakokinetik • Pharmakologie • Pharmazeutische Statistik • Physiologically Based Pharmacokinetic Modeling • PK/PD computer simulations • PK/PD models • predictive models for drug-drug interactions • Sara Rosenbaum • Statistics • Statistik • Transporters |
| ISBN-10 | 1-119-14316-0 / 1119143160 |
| ISBN-13 | 978-1-119-14316-1 / 9781119143161 |
| Haben Sie eine Frage zum Produkt? |
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