Series Editors Preface xi
Preface xiii
Acknowledgements xv
List of Abbreviations xvii

1 Introduction to the Science of Pharmacology 1
1.1 Essentials of Reaction Kinetics 5
1.1.1 Reaction Orders 5
1.1.2 Reversible Reactions 10
1.1.3 Multistep (Complex or Consecutive) Reactions 14
1.2 Mass Transfer Fundamentals 17
1.2.1 Erratic Particle Movement in Fluids 19
1.2.2 Particle Movement Along Concentration Gradients (Convective Mass Transfer) 20
1.3 Drug Binding Essentials 24
1.3.1 Substrate Binding to Proteins 24
1.3.2 Enzyme- (and Transporter-) Catalyzed Reactions 29
1.4 General Compound Ionization Relationships 53

2 Pharmacokinetic Fundamentals 61
2.1 Basic Elements of Pharmacokinetics 61
2.1.1 General Principles of Drug Concentration vs. Time Relationships 61
2.1.2 Anatomic Considerations and General Terminologies 62
2.1.3 Drug Removal from the Body 68
2.2 Data Analysis in Pharmacokinetics 81
2.2.1 Compartmental Analysis of Concentration vs. Time Relationships 81
2.2.2 Non-compartmental Data Analysis 139

3 Absorption 145
3.1 Estimating the Extent of Absorption 145
3.1.1 Pre-systemic (Oral) Absorption 145
3.1.2 Bioavailability 153
3.2 Mechanisms of Drug Transport 161
3.2.1 Drug Partitioning 161
3.2.2 Drug Transport Across (Biological) Membranes 163
3.2.3 Additional Factors Influencing Drug Transport 187
3.3 (Oral) Absorption Modeling 201
3.3.1 Simple Absorption Models 201
3.3.2 Complex (Mechanistic or Theoretical) Absorption Models 208
3.4 Absorption Classification Systems 221
3.4.1 Biopharmaceutics Classification System (BCS) 221
3.4.2 Developability Classification System (DCS) 225

4 Distribution 235
4.1 Descriptors of Protein Binding 235
4.1.1 Protein Occupancy 235Contents vii
4.1.2 Fractional Protein Binding 243
4.1.3 Protein Binding in Blood 257
4.1.4 Protein Binding in Tissues 266
4.1.5 Protein Turnover 273
4.2 Volume of Distribution 275
4.2.1 Initial (or Central) Volume of Distribution, Vdc 276
4.2.2 Volume of Distribution at Steady State, Vdss 278
4.2.3 Volume of Distribution at Pseudo Steady State or Pseudo-Equilibrium, Vd area 286
4.2.4 Extrapolated Volume of Distribution, Vdextra 288
4.3 Drug Delivery to the Brain 288
4.4 Enterohepatic Circulation 303

5 Elimination 313
5.1 Clearance 314
5.1.1 Systemic (Total Body) Clearance 315
5.1.2 Organ Clearance Concepts 318
5.2 Metabolism 352
5.3 Excretion 366
5.3.1 Renal Excretion 369
5.3.2 Biliary Excretion 376

6 PK Forecasting Concepts 383
6.1 Drug Disposition Classification Systems 383
6.1.1 Lipinski's Rule of Five 383
6.1.2 The Biopharmaceutics Drug Disposition Classification System (BDDCS) 384
6.1.3 Extended Clearance Classification System (ECCS or EC2S) 385
6.1.4 Extended Clearance Concept Classification System (ECCCS or EC3S) 386
6.2 Prediction of Human Pharmacokinetics 389
6.2.1 Prediction of Individual PK Parameters 390
6.2.2 Prediction of Plasma-Concentration Profiles 400

7 Pharmacodynamics 413
7.1 Receptor Binding Fundamentals 415
7.1.1 Ordinary Drug–Receptor Models 415
7.1.2 Atypical (Extraordinary or Unusual) Concentration-Effect Relationships 430
7.2 In Vivo Pharmacology 432
7.2.1 Dose Titration (or Static Dose–Response) Model 435
7.2.2 Open Response Models 437
7.2.3 Safety Indices 447
7.2.4 Concepts for Establishing (Clinically) Relevant Dosage Regimen 455

8 Drug–Drug Interactions 463
8.1 Pharmacokinetic Interactions 463
8.1.1 Pharmacokinetic Interaction Mechanisms 465
8.1.2 Quantifying Drug–Drug Interactions 493
8.2 Pharmacodynamic Drug–Drug Interactions 522
8.2.1 Pharmacodynamics in the Presence of Negative Modulators 523
8.2.2 Pharmacodynamics in the Presence of Positive Modulators 531
8.2.3 Measures of Pharmacodynamic Drug–Drug Interactions 532Contents ix

Appendicies 545

A Engineering Technologies 547
A.1 New Chemical Modalities 547
A.2 Genetically Modified Organisms 548
A.3 Microphysiological Systems 548
A.4 Isotopic Labeling 549

B Research and Development Process 553

C Chemistry 561
C.1 Acids and Bases 561
C.2 Oxidants and Reductants 561
C.3 Isomerism 561
C.4 Analytical Chemistry 564

D Mathematical Sciences 577
D.1 Probability Distribution 577
D.2 Statistical Modeling 582
D.3 Algebra 587
D.4 Calculus 588

E Expression of Enzyme and Transporter Proteins 591
E.1 Liver 591
E.2 Intestine 592
E.3 Kidney 593
E.4 Brain and Blood–Brain Barrier 594
E.5 Lung 595
E.6 Blood/Plasma 595

References 596
Index 597