{"product_id":"basic-pharmacokinetics-and-pharmacodynamics-9781119143154","title":"Basic Pharmacokinetics and Pharmacodynamics","description":"\u003cb\u003eBook Synopsis\u003c\/b\u003e\u003cbr\u003eThis book provides a comprehensive foundation for the contemporary application of pharmacokinetics and pharmacodynamics. The second edition updates and strengthens existing chapters and adds new topics to address current needs     including physiologically based pharmacokinetic modeling, pharmacogenomics and predicting drug-drug interactions.\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTable of Contents\u003c\/b\u003e\u003cbr\u003e\u003cp\u003ePreface xix\u003c\/p\u003e \u003cp\u003eContributors xxi\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Introduction to Pharmacokinetics and Pharmacodynamics 1\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction: Drugs and Doses 2\u003c\/p\u003e \u003cp\u003e1.2 Introduction to Pharmacodynamics 3\u003c\/p\u003e \u003cp\u003e1.2.1 Drug Effects at the Site of Action 3\u003c\/p\u003e \u003cp\u003e1.2.2 Agonists, Antagonists, and Concentration–Response Relationships 6\u003c\/p\u003e \u003cp\u003e1.3 Introduction to Pharmacokinetics 9\u003c\/p\u003e \u003cp\u003e1.3.1 Plasma Concentration of Drugs 9\u003c\/p\u003e \u003cp\u003e1.3.2 Processes in Pharmacokinetics 11\u003c\/p\u003e \u003cp\u003e1.4 Dose–Response Relationships 12\u003c\/p\u003e \u003cp\u003e1.5 Therapeutic Range 14\u003c\/p\u003e \u003cp\u003e1.5.1 Determination of the Therapeutic Range 15\u003c\/p\u003e \u003cp\u003e1.6 Summary 18\u003c\/p\u003e \u003cp\u003eReference 18\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Passage of Drugs Through Membranes 19\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction 20\u003c\/p\u003e \u003cp\u003e2.2 Structure and Properties of Membranes 20\u003c\/p\u003e \u003cp\u003e2.3 Passive Diffusion 21\u003c\/p\u003e \u003cp\u003e2.3.1 Transcellular Passive Diffusion 23\u003c\/p\u003e \u003cp\u003e2.3.2 Paracellular Passive Diffusion 25\u003c\/p\u003e \u003cp\u003e2.4 Carrier-Mediated Processes: Transport Proteins 26\u003c\/p\u003e \u003cp\u003e2.4.1 Uptake Transporters: SLC Superfamily 27\u003c\/p\u003e \u003cp\u003e2.4.2 Efflux Transporters: ABC Superfamily 29\u003c\/p\u003e \u003cp\u003e2.4.3 Characteristics of Transporter Systems 31\u003c\/p\u003e \u003cp\u003e2.4.4 Simulation Exercise 32\u003c\/p\u003e \u003cp\u003e2.4.5 Clinical Examples of Transporter Involvement in Drug Response 32\u003c\/p\u003e \u003cp\u003eReferences 33\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Drug Administration and Drug Absorption 35\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSteven C. Sutton\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction: Local and Systemic Drug Administration 36\u003c\/p\u003e \u003cp\u003e3.2 Routes of Drug Administration 37\u003c\/p\u003e \u003cp\u003e3.2.1 Common Routes of Local Drug Administration 37\u003c\/p\u003e \u003cp\u003e3.2.2 Common Routes of Systemic Drug Administration 38\u003c\/p\u003e \u003cp\u003e3.3 Overview of Oral Absorption 41\u003c\/p\u003e \u003cp\u003e3.3.1 Anatomy and Physiology of the Oral-Gastric-Intestinal Tract and Transit Time 41\u003c\/p\u003e \u003cp\u003e3.4 Extent of Drug Absorption 44\u003c\/p\u003e \u003cp\u003e3.4.1 Bioavailability Factor 44\u003c\/p\u003e \u003cp\u003e3.4.2 Individual Bioavailability Factors 45\u003c\/p\u003e \u003cp\u003e3.5 Determinants of the Fraction of the Dose Absorbed (\u003ci\u003eF\u003c\/i\u003e) 46\u003c\/p\u003e \u003cp\u003e3.5.1 Disintegration 46\u003c\/p\u003e \u003cp\u003e3.5.2 Dissolution 46\u003c\/p\u003e \u003cp\u003e3.5.3 Formulation Excipients 50\u003c\/p\u003e \u003cp\u003e3.5.4 Adverse Events within the Gastrointestinal Lumen 50\u003c\/p\u003e \u003cp\u003e3.5.5 Transcellular Passive Diffusion 53\u003c\/p\u003e \u003cp\u003e3.5.6 Particulate Uptake 53\u003c\/p\u003e \u003cp\u003e3.5.7 Paracellular Passive Diffusion 53\u003c\/p\u003e \u003cp\u003e3.5.8 Uptake and Efflux Transporters 54\u003c\/p\u003e \u003cp\u003e3.5.9 Presystemic Intestinal Metabolism or Extraction 58\u003c\/p\u003e \u003cp\u003e3.5.10 Presystemic Hepatic Metabolism or Extraction 60\u003c\/p\u003e \u003cp\u003e3.6 Factors Controlling the Rate of Drug Absorption 61\u003c\/p\u003e \u003cp\u003e3.6.1 Dissolution-Controlled Absorption 63\u003c\/p\u003e \u003cp\u003e3.6.2 Membrane Penetration-Controlled Absorption 63\u003c\/p\u003e \u003cp\u003e3.6.3 Overall Rate of Drug Absorption 63\u003c\/p\u003e \u003cp\u003e3.7 Biopharmaceutics Classification System 64\u003c\/p\u003e \u003cp\u003e3.7.1 Intestinal Reserve Length 64\u003c\/p\u003e \u003cp\u003e3.7.2 Biopharmaceutics Classification System (BCS) 64\u003c\/p\u003e \u003cp\u003e3.7.3 Biopharmaceutics Drug Disposition Classification System (BDDCS) 65\u003c\/p\u003e \u003cp\u003e3.8 Food Effects 65\u003c\/p\u003e \u003cp\u003eProblems 66\u003c\/p\u003e \u003cp\u003eReferences 67\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Drug Distribution 71\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 72\u003c\/p\u003e \u003cp\u003e4.2 Extent of Drug Distribution 72\u003c\/p\u003e \u003cp\u003e4.2.1 Distribution Volumes 74\u003c\/p\u003e \u003cp\u003e4.2.2 Tissue Binding Plasma Protein Binding and Partitioning: Concentrating Effects 75\u003c\/p\u003e \u003cp\u003e4.2.3 Assessment of the Extent of Drug Distribution: Apparent Volume of Distribution 76\u003c\/p\u003e \u003cp\u003e4.2.4 Plasma Protein Binding 82\u003c\/p\u003e \u003cp\u003e4.3 Rate of Drug Distribution 89\u003c\/p\u003e \u003cp\u003e4.3.1 Perfusion-Controlled Drug Distribution 90\u003c\/p\u003e \u003cp\u003e4.3.2 Diffusion or Permeability-Controlled Drug Distribution 93\u003c\/p\u003e \u003cp\u003e4.4 Distribution of Drugs to the Central Nervous System 93\u003c\/p\u003e \u003cp\u003eProblems 96\u003c\/p\u003e \u003cp\u003eReferences 98\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Drug Elimination and Clearance 99\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 100\u003c\/p\u003e \u003cp\u003e5.1.1 First-Order Elimination 101\u003c\/p\u003e \u003cp\u003e5.1.2 Determinants of the Elimination Rate Constant and the Half-Life 102\u003c\/p\u003e \u003cp\u003e5.2 Clearance 102\u003c\/p\u003e \u003cp\u003e5.2.1 Definition and Determinants of Clearance 102\u003c\/p\u003e \u003cp\u003e5.2.2 Total Clearance, Renal Clearance, and Hepatic Clearance 104\u003c\/p\u003e \u003cp\u003e5.2.3 Relationships among Clearance, Volume of Distribution, Elimination Rate Constant, and Half-Life 105\u003c\/p\u003e \u003cp\u003e5.2.4 Primary and Secondary Parameters 106\u003c\/p\u003e \u003cp\u003e5.2.5 Measurement of Total Body Clearance 106\u003c\/p\u003e \u003cp\u003e5.3 Renal Clearance 108\u003c\/p\u003e \u003cp\u003e5.3.1 Glomerular Filtration 109\u003c\/p\u003e \u003cp\u003e5.3.2 Tubular Secretion 110\u003c\/p\u003e \u003cp\u003e5.3.3 Tubular Reabsorption 113\u003c\/p\u003e \u003cp\u003e5.3.4 Putting Meaning into the Value of Renal Clearance 114\u003c\/p\u003e \u003cp\u003e5.3.5 Measurement of Renal Clearance 115\u003c\/p\u003e \u003cp\u003e5.3.6 Fraction of the Dose Excreted Unchanged 118\u003c\/p\u003e \u003cp\u003e5.4 Hepatic Elimination and Clearance 119\u003c\/p\u003e \u003cp\u003e5.4.1 Phase I and Phase II Metabolism 120\u003c\/p\u003e \u003cp\u003e5.4.2 The Cytochrome P450 Enzyme System 121\u003c\/p\u003e \u003cp\u003e5.4.3 Glucuronidation 122\u003c\/p\u003e \u003cp\u003e5.4.4 Metabolism-Based Drug–Drug Interactions 122\u003c\/p\u003e \u003cp\u003e5.4.5 Hepatic Drug Transporters and Drug–Drug Interactions 125\u003c\/p\u003e \u003cp\u003e5.4.6 Kinetics of Drug Metabolism 127\u003c\/p\u003e \u003cp\u003e5.4.7 Hepatic Clearance and Related Parameters 128\u003c\/p\u003e \u003cp\u003eProblems 139\u003c\/p\u003e \u003cp\u003eReferences 142\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Compartmental Models in Pharmacokinetics 145\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 146\u003c\/p\u003e \u003cp\u003e6.2 Expressions for Component Parts of the Dose–Plasma Concentration Relationship 146\u003c\/p\u003e \u003cp\u003e6.2.1 Effective Dose 146\u003c\/p\u003e \u003cp\u003e6.2.2 Rate of Drug Absorption 147\u003c\/p\u003e \u003cp\u003e6.2.3 Rate of Drug Elimination 148\u003c\/p\u003e \u003cp\u003e6.2.4 Rate of Drug Distribution 148\u003c\/p\u003e \u003cp\u003e6.3 Putting Everything Together: Compartments and Models 149\u003c\/p\u003e \u003cp\u003e6.3.1 One-Compartment Model 149\u003c\/p\u003e \u003cp\u003e6.3.2 Two-Compartment Model 150\u003c\/p\u003e \u003cp\u003e6.3.3 Three-Compartment Model 150\u003c\/p\u003e \u003cp\u003e6.4 Examples of Complete Compartment Models 152\u003c\/p\u003e \u003cp\u003e6.4.1 Intravenous Bolus Injection in a One-Compartment Model with First-Order Elimination 152\u003c\/p\u003e \u003cp\u003e6.4.2 Intravenous Bolus Injection in a Two-Compartment Model with First-Order Elimination 153\u003c\/p\u003e \u003cp\u003e6.4.3 First-Order Absorption in a Two-Compartment Model with First-Order Elimination 154\u003c\/p\u003e \u003cp\u003e6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics 155\u003c\/p\u003e \u003cp\u003e6.6 Selecting and Applying Models 156\u003c\/p\u003e \u003cp\u003eProblems 157\u003c\/p\u003e \u003cp\u003eSuggested Readings 157\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Pharmacokinetics of an Intravenous Bolus Injection in a One-Compartment Model 159\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 160\u003c\/p\u003e \u003cp\u003e7.2 One-Compartment Model 160\u003c\/p\u003e \u003cp\u003e7.3 Pharmacokinetic Equations 162\u003c\/p\u003e \u003cp\u003e7.3.1 Basic Equation 162\u003c\/p\u003e \u003cp\u003e7.3.2 Half-Life 163\u003c\/p\u003e \u003cp\u003e7.3.3 Time to Eliminate a Dose 163\u003c\/p\u003e \u003cp\u003e7.4 Simulation Exercise 163\u003c\/p\u003e \u003cp\u003e7.5 Application of the Model 165\u003c\/p\u003e \u003cp\u003e7.5.1 Predicting Plasma Concentrations 165\u003c\/p\u003e \u003cp\u003e7.5.2 Duration of Action 166\u003c\/p\u003e \u003cp\u003e7.5.3 Value of a Dose to Give a Desired Initial Plasma Concentration 167\u003c\/p\u003e \u003cp\u003e7.5.4 Intravenous Loading Dose 167\u003c\/p\u003e \u003cp\u003e7.6 Determination of Pharmacokinetic Parameters Experimentally 168\u003c\/p\u003e \u003cp\u003e7.6.1 Study Design for the Determination of Parameters 168\u003c\/p\u003e \u003cp\u003e7.6.2 Pharmacokinetic Analysis 169\u003c\/p\u003e \u003cp\u003e7.7 Pharmacokinetic Analysis in Clinical Practice 173\u003c\/p\u003e \u003cp\u003eProblems 174\u003c\/p\u003e \u003cp\u003eSuggested Reading 176\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Pharmacokinetics of an Intravenous Bolus Injection in a Two-Compartment Model 177\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 178\u003c\/p\u003e \u003cp\u003e8.2 Tissue and Compartmental Distribution of a Drug 179\u003c\/p\u003e \u003cp\u003e8.2.1 Drug Distribution to the Tissues 179\u003c\/p\u003e \u003cp\u003e8.2.2 Compartmental Distribution of a Drug 180\u003c\/p\u003e \u003cp\u003e8.3 Basic Equation 181\u003c\/p\u003e \u003cp\u003e8.3.1 Distribution: \u003ci\u003eA,\u003c\/i\u003e α, and the Distribution \u003ci\u003et\u003c\/i\u003e\u003csub\u003e1\/2\u003c\/sub\u003e 182\u003c\/p\u003e \u003cp\u003e8.3.2 Elimination: \u003ci\u003eB,\u003c\/i\u003e β, and the β \u003ci\u003et\u003c\/i\u003e\u003csub\u003e1\/2\u003c\/sub\u003e 182\u003c\/p\u003e \u003cp\u003e8.4 Relationship Between Macro and Micro Rate Constants 183\u003c\/p\u003e \u003cp\u003e8.5 Primary Pharmacokinetic Parameters 183\u003c\/p\u003e \u003cp\u003e8.5.1 Clearance 184\u003c\/p\u003e \u003cp\u003e8.5.2 Distribution Clearance 184\u003c\/p\u003e \u003cp\u003e8.5.3 Volume of Distribution 186\u003c\/p\u003e \u003cp\u003e8.6 Simulation Exercise 188\u003c\/p\u003e \u003cp\u003e8.7 Determination of the Pharmacokinetic Parameters of the Two-Compartment Model 191\u003c\/p\u003e \u003cp\u003e8.7.1 Determination of Intercepts and Macro Rate Constants 191\u003c\/p\u003e \u003cp\u003e8.7.2 Determination of the Micro Rate Constants: \u003ci\u003ek\u003c\/i\u003e\u003csub\u003e12\u003c\/sub\u003e \u003ci\u003ek\u003c\/i\u003e\u003csub\u003e21\u003c\/sub\u003e and \u003ci\u003ek\u003c\/i\u003e\u003csub\u003e10\u003c\/sub\u003e 193\u003c\/p\u003e \u003cp\u003e8.7.3 Determination of the Primary Pharmacokinetic Parameters 193\u003c\/p\u003e \u003cp\u003e8.8 Clinical Application of the Two-Compartment Model 194\u003c\/p\u003e \u003cp\u003e8.8.1 Measurement of the Elimination Half-Life in the Postdistribution Phase 194\u003c\/p\u003e \u003cp\u003e8.8.2 Determination of the Loading Dose 195\u003c\/p\u003e \u003cp\u003e8.8.3 Evaluation of a Dose: Monitoring Plasma Concentrations and Patient Response 197\u003c\/p\u003e \u003cp\u003eProblems 197\u003c\/p\u003e \u003cp\u003eSuggested Readings 199\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Pharmacokinetics of Extravascular Drug Administration 201\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDr. Steven C. Sutton\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 202\u003c\/p\u003e \u003cp\u003e9.2 First-Order Absorption in a One-Compartment Model 203\u003c\/p\u003e \u003cp\u003e9.2.1 Model and Equations 203\u003c\/p\u003e \u003cp\u003e9.2.2 Parameter Determination 205\u003c\/p\u003e \u003cp\u003e9.2.3 Absorption Lag Time 210\u003c\/p\u003e \u003cp\u003e9.2.4 Flip-Flop Model and Sustained-Release Preparations 212\u003c\/p\u003e \u003cp\u003e9.2.5 Determinants of \u003ci\u003eT\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e and \u003ci\u003eC\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e 212\u003c\/p\u003e \u003cp\u003e9.3 Modified Release and Gastric Retention Formulations 214\u003c\/p\u003e \u003cp\u003e9.3.1 Impact of the Stomach 214\u003c\/p\u003e \u003cp\u003e9.3.2 Moisture in the Gastrointestinal Tract 215\u003c\/p\u003e \u003cp\u003e9.4 Bioavailability 215\u003c\/p\u003e \u003cp\u003e9.4.1 Bioavailability Parameters 215\u003c\/p\u003e \u003cp\u003e9.4.2 Absolute Bioavailability 217\u003c\/p\u003e \u003cp\u003e9.4.3 Relative Bioavailability 217\u003c\/p\u003e \u003cp\u003e9.4.4 Bioequivalence 217\u003c\/p\u003e \u003cp\u003e9.4.5 Single-Dose Crossover Parallel and Steady-State Study Designs 219\u003c\/p\u003e \u003cp\u003e9.4.6 Example Bioavailability Analysis 219\u003c\/p\u003e \u003cp\u003e9.5 \u003ci\u003eIn Vitro-In Vivo \u003c\/i\u003eCorrelation 219\u003c\/p\u003e \u003cp\u003e9.5.1 Definitions 219\u003c\/p\u003e \u003cp\u003e9.5.2 Assumptions 220\u003c\/p\u003e \u003cp\u003e9.5.3 Utility 220\u003c\/p\u003e \u003cp\u003e9.5.4 Immediate Release IVIVC 220\u003c\/p\u003e \u003cp\u003e9.5.5 Modified Release IVIVC 221\u003c\/p\u003e \u003cp\u003e9.6 Simulation Exercise 222\u003c\/p\u003e \u003cp\u003eProblems 223\u003c\/p\u003e \u003cp\u003eReferences 224\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Introduction to Noncompartmental Analysis 225\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 225\u003c\/p\u003e \u003cp\u003e10.2 Mean Residence Time 226\u003c\/p\u003e \u003cp\u003e10.3 Determination of Other Important Pharmacokinetic Parameters 229\u003c\/p\u003e \u003cp\u003e10.4 Different Routes of Administration 231\u003c\/p\u003e \u003cp\u003e10.5 Application of Noncompartmental Analysis to Clinical Studies 232\u003c\/p\u003e \u003cp\u003eProblems 234\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Pharmacokinetics of Intravenous Infusion in a One-Compartment Model 237\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 238\u003c\/p\u003e \u003cp\u003e11.2 Model and Equations 239\u003c\/p\u003e \u003cp\u003e11.2.1 Basic Equation 239\u003c\/p\u003e \u003cp\u003e11.2.2 Application of the Basic Equation 241\u003c\/p\u003e \u003cp\u003e11.2.3 Simulation Exercise: Part 1 241\u003c\/p\u003e \u003cp\u003e11.3 Steady-State Plasma Concentration 242\u003c\/p\u003e \u003cp\u003e11.3.1 Equation for Steady-State Plasma Concentrations 242\u003c\/p\u003e \u003cp\u003e11.3.2 Application of the Equation 242\u003c\/p\u003e \u003cp\u003e11.3.3 Basic Formula Revisited 243\u003c\/p\u003e \u003cp\u003e11.3.4 Factors Controlling Steady-State Plasma Concentration 243\u003c\/p\u003e \u003cp\u003e11.3.5 Time to Steady State 244\u003c\/p\u003e \u003cp\u003e11.3.6 Simulation Exercise: Part 2 245\u003c\/p\u003e \u003cp\u003e11.4 Loading Dose 246\u003c\/p\u003e \u003cp\u003e11.4.1 Loading-Dose Equation 246\u003c\/p\u003e \u003cp\u003e11.4.2 Simulation Exercise: Part 3 248\u003c\/p\u003e \u003cp\u003e11.5 Termination of Infusion 248\u003c\/p\u003e \u003cp\u003e11.5.1 Equations for Termination Before and After Steady State 248\u003c\/p\u003e \u003cp\u003e11.5.2 Simulation Exercise: Part 4 249\u003c\/p\u003e \u003cp\u003e11.6 Individualization of Dosing Regimens 249\u003c\/p\u003e \u003cp\u003e11.6.1 Initial Doses 249\u003c\/p\u003e \u003cp\u003e11.6.2 Monitoring and Individualizing Therapy 250\u003c\/p\u003e \u003cp\u003eProblems 252\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Multiple Intravenous Bolus Injections in the One-Compartment Model 255\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 256\u003c\/p\u003e \u003cp\u003e12.2 Terms and Symbols Used in Multiple-Dosing Equations 257\u003c\/p\u003e \u003cp\u003e12.3 Monoexponential Decay During a Dosing Interval 259\u003c\/p\u003e \u003cp\u003e12.3.1 Calculation of Dosing Interval to Give Specific Steady-State Peaks and Troughs 260\u003c\/p\u003e \u003cp\u003e12.4 Basic Pharmacokinetic Equations for Multiple Doses 260\u003c\/p\u003e \u003cp\u003e12.4.1 Principle of Superposition 260\u003c\/p\u003e \u003cp\u003e12.4.2 Equations that Apply Before Steady State 261\u003c\/p\u003e \u003cp\u003e12.5 Steady State 262\u003c\/p\u003e \u003cp\u003e12.5.1 Steady-State Equations 263\u003c\/p\u003e \u003cp\u003e12.5.2 Average Plasma Concentration at Steady State 264\u003c\/p\u003e \u003cp\u003e12.5.3 Fluctuation 267\u003c\/p\u003e \u003cp\u003e12.5.4 Accumulation 267\u003c\/p\u003e \u003cp\u003e12.5.5 Time to Reach Steady State 269\u003c\/p\u003e \u003cp\u003e12.5.6 Loading Dose 270\u003c\/p\u003e \u003cp\u003e12.6 Basic Formula Revisited 270\u003c\/p\u003e \u003cp\u003e12.7 Pharmacokinetic-Guided Dosing Regimen Design 270\u003c\/p\u003e \u003cp\u003e12.7.1 General Considerations for Selection of the Dosing Interval 270\u003c\/p\u003e \u003cp\u003e12.7.2 Protocols for Pharmacokinetic-Guided Dosing Regimens 272\u003c\/p\u003e \u003cp\u003e12.8 Simulation Exercise 276\u003c\/p\u003e \u003cp\u003eProblems 277\u003c\/p\u003e \u003cp\u003eReference 278\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Multiple Intermittent Infusions 279\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 279\u003c\/p\u003e \u003cp\u003e13.2 Steady-State Equations for Multiple Intermittent Infusions 281\u003c\/p\u003e \u003cp\u003e13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks Troughs and Elimination Half-Life 284\u003c\/p\u003e \u003cp\u003e13.3.1 Determination of Half-Life 284\u003c\/p\u003e \u003cp\u003e13.3.2 Determination of Peaks and Troughs 286\u003c\/p\u003e \u003cp\u003e13.4 Determination of the Volume of Distribution 286\u003c\/p\u003e \u003cp\u003e13.5 Individualization of Dosing Regimens 289\u003c\/p\u003e \u003cp\u003e13.6 Simulation 289\u003c\/p\u003e \u003cp\u003eProblems 290\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Multiple Oral Doses 293\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 293\u003c\/p\u003e \u003cp\u003e14.2 Steady-State Equations 294\u003c\/p\u003e \u003cp\u003e14.2.1 Time to Peak Steady-State Plasma Concentration 295\u003c\/p\u003e \u003cp\u003e14.2.2 Maximum Steady-State Plasma Concentration 296\u003c\/p\u003e \u003cp\u003e14.2.3 Minimum Steady-State Plasma Concentration 296\u003c\/p\u003e \u003cp\u003e14.2.4 Average Steady-State Plasma Concentration 296\u003c\/p\u003e \u003cp\u003e14.2.5 Overall Effect of Absorption Parameters on a Steady-State Dosing Interval 297\u003c\/p\u003e \u003cp\u003e14.3 Equations Used Clinically to Individualize Oral Doses 298\u003c\/p\u003e \u003cp\u003e14.3.1 Protocol to Select an Appropriate Equation 298\u003c\/p\u003e \u003cp\u003e14.4 Simulation Exercise 300\u003c\/p\u003e \u003cp\u003eReferences 301\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Nonlinear Pharmacokinetics 303\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Linear Pharmacokinetics 304\u003c\/p\u003e \u003cp\u003e15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination 306\u003c\/p\u003e \u003cp\u003e15.3 Pharmacokinetics of Capacity-Limited Metabolism 307\u003c\/p\u003e \u003cp\u003e15.3.1 Kinetics of Enzymatic Processes 307\u003c\/p\u003e \u003cp\u003e15.3.2 Plasma Concentration–Time Profile 309\u003c\/p\u003e \u003cp\u003e15.4 Phenytoin 310\u003c\/p\u003e \u003cp\u003e15.4.1 Basic Equation for Steady State 311\u003c\/p\u003e \u003cp\u003e15.4.2 Estimation of Doses and Plasma Concentrations 313\u003c\/p\u003e \u003cp\u003e15.4.3 Influence of \u003ci\u003eK\u003csub\u003em\u003c\/sub\u003e \u003c\/i\u003eand \u003ci\u003eV\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e and Factors That Affect These Parameters 314\u003c\/p\u003e \u003cp\u003e15.4.4 Time to Eliminate the Drug 316\u003c\/p\u003e \u003cp\u003e15.4.5 Time to Reach Steady State 317\u003c\/p\u003e \u003cp\u003e15.4.6 Individualization of Doses of Phenytoin 318\u003c\/p\u003e \u003cp\u003eProblems 321\u003c\/p\u003e \u003cp\u003eReferences 322\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Introduction to Pharmacogenetics 323\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDr. Daniel Brazeau\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 324\u003c\/p\u003e \u003cp\u003e16.2 Genetics Primer 324\u003c\/p\u003e \u003cp\u003e16.2.1 Basic Terminology: Genes Alleles Loci and Polymorphism 324\u003c\/p\u003e \u003cp\u003e16.2.2 Population Genetics: Allele and Genotype Frequencies 326\u003c\/p\u003e \u003cp\u003e16.2.3 Quantitative Genetics and Complex Traits 327\u003c\/p\u003e \u003cp\u003e16.3 Pharmacogenetics 328\u003c\/p\u003e \u003cp\u003e16.3.1 Pharmacogenetics of Drug-Metabolizing Enzymes 330\u003c\/p\u003e \u003cp\u003e16.3.2 Pharmacogenetics of Drug Transporters 333\u003c\/p\u003e \u003cp\u003e16.4 Genetics and Pharmacodynamics 334\u003c\/p\u003e \u003cp\u003e16.4.1 Drug Target Pharmacogenetics 334\u003c\/p\u003e \u003cp\u003e16.5 Summary 335\u003c\/p\u003e \u003cp\u003eReference 335\u003c\/p\u003e \u003cp\u003eSuggested Readings 335\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Models Used to Predict Drug–Drug Interactions for Orally Administered Drugs 337\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 338\u003c\/p\u003e \u003cp\u003e17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism Based on \u003ci\u003eIn Vitro \u003c\/i\u003eData 340\u003c\/p\u003e \u003cp\u003e17.2.1 Reversible Inhibition 340\u003c\/p\u003e \u003cp\u003e17.2.2 Time-Dependent Inhibition 341\u003c\/p\u003e \u003cp\u003e17.2.3 Induction 345\u003c\/p\u003e \u003cp\u003e17.3 Surrogate \u003ci\u003eIn Vivo \u003c\/i\u003eValues for the Unbound Concentration of the Perpetrator at the Site of Action 345\u003c\/p\u003e \u003cp\u003e17.3.1 Surrogate Measures of Hepatic Inhibitor and Inducer Concentrations 346\u003c\/p\u003e \u003cp\u003e17.3.2 Surrogate Measures of Intestinal Inhibitor and Inducer Concentrations 346\u003c\/p\u003e \u003cp\u003e17.4 Models Used to Predict DDIs \u003ci\u003eIn Vivo\u003c\/i\u003e 347\u003c\/p\u003e \u003cp\u003e17.4.1 Introduction 347\u003c\/p\u003e \u003cp\u003e17.4.2 Basic Predictive Models: \u003ci\u003eR \u003c\/i\u003eValues 348\u003c\/p\u003e \u003cp\u003e17.4.3 Predictive Models Incorporating Parallel Pathways of Elimination (\u003ci\u003efm\u003c\/i\u003e) 350\u003c\/p\u003e \u003cp\u003e17.4.4 Models Incorporating Intestinal Extraction 354\u003c\/p\u003e \u003cp\u003e17.4.5 Models Combining Multiple Actions of Perpetrators 358\u003c\/p\u003e \u003cp\u003e17.5 Predictive Models for Transporter-Based DDIs 359\u003c\/p\u003e \u003cp\u003e17.5.1 Kinetics of Drug Transporters 359\u003c\/p\u003e \u003cp\u003e17.6 Application of Physiologically Based Pharmacokinetic Models to DDI Prediction: The Dynamic Approach 362\u003c\/p\u003e \u003cp\u003e17.7 Conclusion 362\u003c\/p\u003e \u003cp\u003eProblems 363\u003c\/p\u003e \u003cp\u003eReferences 364\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Introduction to Physiologically Based Pharmacokinetic Modeling 367\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 368\u003c\/p\u003e \u003cp\u003e18.2 Components of PBPK Models 369\u003c\/p\u003e \u003cp\u003e18.3 Equations for PBPK Models 369\u003c\/p\u003e \u003cp\u003e18.4 Building a PBPK Model 373\u003c\/p\u003e \u003cp\u003e18.5 Simulations 377\u003c\/p\u003e \u003cp\u003e18.6 Estimation of Human Drug-Specific Parameters 378\u003c\/p\u003e \u003cp\u003e18.6.1 Tissue Plasma Partition Coefficient 379\u003c\/p\u003e \u003cp\u003e18.6.2 Volume of Distribution 379\u003c\/p\u003e \u003cp\u003e18.6.3 Clearance 380\u003c\/p\u003e \u003cp\u003e18.7 More Detailed PBPK Models 381\u003c\/p\u003e \u003cp\u003e18.7.1 Permeability-Limited Distribution 381\u003c\/p\u003e \u003cp\u003e18.7.2 Drug Transporters 383\u003c\/p\u003e \u003cp\u003e18.7.3 Models for Oral Absorption 386\u003c\/p\u003e \u003cp\u003e18.7.4 Reduced Models 387\u003c\/p\u003e \u003cp\u003e18.8 Application of PBPK Models 387\u003c\/p\u003e \u003cp\u003eReferences 388\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic–Pharmacodynamic Models 391\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDrs. Diane Mould and Paul Hutson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 392\u003c\/p\u003e \u003cp\u003e19.2 Classic Pharmacodynamic Models Based on Receptor Theory 393\u003c\/p\u003e \u003cp\u003e19.2.1 Receptor Binding 394\u003c\/p\u003e \u003cp\u003e19.2.2 Concentration-Response Models 395\u003c\/p\u003e \u003cp\u003e19.3 Direct Effect Pharmacodynamic Models 402\u003c\/p\u003e \u003cp\u003e19.3.1 \u003ci\u003eE\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e and Sigmoidal \u003ci\u003eE\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e Models 402\u003c\/p\u003e \u003cp\u003e19.3.2 Inhibitory \u003ci\u003eI\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e and Sigmoidal \u003ci\u003eI\u003c\/i\u003emax Models 404\u003c\/p\u003e \u003cp\u003e19.3.3 Linear Adaptations of the \u003ci\u003eE\u003c\/i\u003emax and \u003ci\u003eI\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e Model 404\u003c\/p\u003e \u003cp\u003e19.4 Integrated PK–PD Models: Intravenous Bolus Injection in the One-Compartment Model and the Sigmoidal \u003ci\u003eE\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e Model 406\u003c\/p\u003e \u003cp\u003e19.4.1 Simulation Exercise 409\u003c\/p\u003e \u003cp\u003e19.5 Pharmacodynamic Drug–Drug Interactions 410\u003c\/p\u003e \u003cp\u003e19.5.1 Simulation Exercise 410\u003c\/p\u003e \u003cp\u003eProblems 411\u003c\/p\u003e \u003cp\u003eReferences 412\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Semimechanistic Pharmacokinetic–Pharmacodynamic Models 413\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDrs. Diane Mould and Paul Hutson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 414\u003c\/p\u003e \u003cp\u003e20.2 Hysteresis and the Effect Compartment 416\u003c\/p\u003e \u003cp\u003e20.2.1 Simulation Exercise 419\u003c\/p\u003e \u003cp\u003e20.3 Physiological Turnover Models and Their Characteristics 419\u003c\/p\u003e \u003cp\u003e20.3.1 Points of Drug Action 421\u003c\/p\u003e \u003cp\u003e20.3.2 System Recovery After Change in Baseline Value 421\u003c\/p\u003e \u003cp\u003e20.4 Indirect Effect Models 422\u003c\/p\u003e \u003cp\u003e20.4.1 Introduction 422\u003c\/p\u003e \u003cp\u003e20.4.2 Characteristics of Indirect Effect Drug Responses 424\u003c\/p\u003e \u003cp\u003e20.4.3 Characteristics of Indirect Effect Models Illustrated Using Model I 426\u003c\/p\u003e \u003cp\u003e20.5 Other Indirect Effect Models 432\u003c\/p\u003e \u003cp\u003e20.5.1 Transit Compartment Models 435\u003c\/p\u003e \u003cp\u003e20.5.2 Model for Hematological Toxicity of Anticancer Drugs 439\u003c\/p\u003e \u003cp\u003e20.5.3 Alternate Parameterizations of Transit Models 442\u003c\/p\u003e \u003cp\u003e20.6 Models of Tolerance 442\u003c\/p\u003e \u003cp\u003e20.6.1 Introduction to Pharmacologic Tolerance 442\u003c\/p\u003e \u003cp\u003e20.6.2 Counter-Regulatory Force Tolerance Model 444\u003c\/p\u003e \u003cp\u003e20.6.3 Precursor Pool Model of Tolerance 447\u003c\/p\u003e \u003cp\u003e20.7 Irreversible Drug Effects 450\u003c\/p\u003e \u003cp\u003e20.7.1 Application of the Turnover Model to Irreversible Drug Action 450\u003c\/p\u003e \u003cp\u003e20.8 Disease Progression Models 452\u003c\/p\u003e \u003cp\u003e20.8.1 Drug Pharmacokinetics 452\u003c\/p\u003e \u003cp\u003e20.8.2 Pharmacodynamics 452\u003c\/p\u003e \u003cp\u003e20.8.3 Disease Activity Models 453\u003c\/p\u003e \u003cp\u003e20.8.4 Disease Progression Models 453\u003c\/p\u003e \u003cp\u003eProblems 459\u003c\/p\u003e \u003cp\u003eReferences 465\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix A Review of Exponents and Logarithms 469\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eA.1 Exponents 469\u003c\/p\u003e \u003cp\u003eA.2 Logarithms: Log and Ln 470\u003c\/p\u003e \u003cp\u003eA.3 Performing Calculations in the Logarithmic Domain 471\u003c\/p\u003e \u003cp\u003eA.3.1 Multiplication 471\u003c\/p\u003e \u003cp\u003eA.3.2 Division 472\u003c\/p\u003e \u003cp\u003eA.3.3 Reciprocals 472\u003c\/p\u003e \u003cp\u003eA.3.4 Exponents 472\u003c\/p\u003e \u003cp\u003eA.4 Calculations Using Exponential Expressions and Logarithms 472\u003c\/p\u003e \u003cp\u003eA.5 Decay Function: \u003ci\u003ee\u003c\/i\u003e\u003csup\u003e−\u003ci\u003ekt\u003c\/i\u003e\u003c\/sup\u003e 474\u003c\/p\u003e \u003cp\u003eA.6 Growth Function: 1 − \u003ci\u003ee\u003c\/i\u003e\u003csup\u003e−\u003ci\u003ekt\u003c\/i\u003e\u003c\/sup\u003e 475\u003c\/p\u003e \u003cp\u003eA.7 Decay Function in Pharmacokinetics 475\u003c\/p\u003e \u003cp\u003eProblems 476\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix B Rates of Processes 479\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eB.1 Introduction 479\u003c\/p\u003e \u003cp\u003eB.2 Order of a Rate Process 480\u003c\/p\u003e \u003cp\u003eB.3 Zero-Order Processes 480\u003c\/p\u003e \u003cp\u003eB.3.1 Equation for Zero-Order Filling 480\u003c\/p\u003e \u003cp\u003eB.3.2 Equation for Zero-Order Emptying 481\u003c\/p\u003e \u003cp\u003eB.3.3 Time for Zero-Order Emptying to Go to 50% Completion 481\u003c\/p\u003e \u003cp\u003eB.4 First-Order Processes 482\u003c\/p\u003e \u003cp\u003eB.4.1 Equation for a First-Order Process 482\u003c\/p\u003e \u003cp\u003eB.4.2 Time for 50% Completion: the Half-Life 483\u003c\/p\u003e \u003cp\u003eB.5 Comparison of Zero- and First-Order Processes 484\u003c\/p\u003e \u003cp\u003eB.6 Detailed Example of First-Order Decay in Pharmacokinetics 484\u003c\/p\u003e \u003cp\u003eB.6.1 Equations and Semilogarithmic Plots 484\u003c\/p\u003e \u003cp\u003eB.6.2 Half-Life 485\u003c\/p\u003e \u003cp\u003eB.6.3 Fraction or Percent Completion of a First-Order Process Using First-Order Elimination as an Example 485\u003c\/p\u003e \u003cp\u003eB.7 Examples of the Application of First-Order Kinetics to Pharmacokinetics 487\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 489\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eC.1 Measurement of AUC and Clearance 489\u003c\/p\u003e \u003cp\u003eC.1.1 Trapezoidal Rule 490\u003c\/p\u003e \u003cp\u003eC.1.2 Excel Spreadsheet to Determine AUC\u003csub\u003e0→∞\u003c\/sub\u003e and Clearance 491\u003c\/p\u003e \u003cp\u003eC.2 Analysis of Data from an Intravenous Bolus Injection in a One-Compartment Model 494\u003c\/p\u003e \u003cp\u003eC.3 Analysis of Data from an Intravenous Bolus Injection in a Two-Compartment Model 496\u003c\/p\u003e \u003cp\u003eC.4 Analysis of Oral Data in a One-Compartment Model 498\u003c\/p\u003e \u003cp\u003eC.5 Noncompartmental Analysis of Oral Data 501\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix D Derivation of Equations for Multiple Intravenous Bolus Injections 505\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eD.1 Assumptions 505\u003c\/p\u003e \u003cp\u003eD.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections 505\u003c\/p\u003e \u003cp\u003eD.3 Steady-State Equations 508\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix E Enzyme Kinetics: Michaelis–Menten Equation and Models for Inhibitors and Inducers of Drug Metabolism 509\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum and Roberta S. King\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eE.1 Kinetics of Drug Metabolism: The Michaelis–Menten Model 510\u003c\/p\u003e \u003cp\u003eE.1.1 Overview 510\u003c\/p\u003e \u003cp\u003eE.1.2 Assumptions for Validity of Michaelis–Menten Model 510\u003c\/p\u003e \u003cp\u003eE.1.3 \u003ci\u003eKm \u003c\/i\u003eand \u003ci\u003eV\u003c\/i\u003emax 511\u003c\/p\u003e \u003cp\u003eE.1.4 Derivation of the Michaelis–Menten Equation 511\u003c\/p\u003e \u003cp\u003eE.1.5 Summary, Practical Considerations, and Interpretations 513\u003c\/p\u003e \u003cp\u003eE.1.6 Relationship Between Intrinsic Clearance and the Michaelis–Menten Parameters 514\u003c\/p\u003e \u003cp\u003eE.2 Effect of Perpetrators of DDI on Enzyme Kinetics and Intrinsic Clearance 515\u003c\/p\u003e \u003cp\u003eE.2.1 Reversible Inhibition 515\u003c\/p\u003e \u003cp\u003eE.2.2 Time-Dependent Inhibition 518\u003c\/p\u003e \u003cp\u003eE.2.3 Enzyme Induction 524\u003c\/p\u003e \u003cp\u003eReferences 526\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix F Summary of the Properties of the Fictitious Drugs Used in the Text 527\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix G Computer Simulation Models 529\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSara E. Rosenbaum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eGlossary of Terms 531\u003c\/p\u003e \u003cp\u003eIndex 537\u003c\/p\u003e","brand":"John Wiley \u0026 Sons Inc","offers":[{"title":"Default Title","offer_id":48866387591511,"sku":"9781119143154","price":62.06,"currency_code":"GBP","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0817\/1739\/5799\/files\/9781119143154.jpg?v=1722278408","url":"https:\/\/bookcurl.com\/products\/basic-pharmacokinetics-and-pharmacodynamics-9781119143154","provider":"Book Curl","version":"1.0","type":"link"}