Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists / Edition 1

Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists / Edition 1

by Younggil Kwon
     
 

ISBN-10: 0306462346

ISBN-13: 9780306462344

Pub. Date: 12/31/2001

Publisher: Springer US

This volume is a handbook primarily designed for scientists and technicians without formal pharmacokinetics/pharmacodynamics (PK/PD) training, who work in an industrial setting. The book is a primary desktop reference and contains easy-to-understand guidance for PK/PD issues, study design, and data interpretation. PK/PD are integral aspects for investigating the

Overview

This volume is a handbook primarily designed for scientists and technicians without formal pharmacokinetics/pharmacodynamics (PK/PD) training, who work in an industrial setting. The book is a primary desktop reference and contains easy-to-understand guidance for PK/PD issues, study design, and data interpretation. PK/PD are integral aspects for investigating the disposition and pharmacological efficacy of drugs under various experimental and clinical conditions

Product Details

ISBN-13:
9780306462344
Publisher:
Springer US
Publication date:
12/31/2001
Edition description:
2002
Pages:
291
Product dimensions:
6.14(w) x 9.21(h) x 0.03(d)

Table of Contents

1.Introduction1
2.Pharmacokinetic Study Design and Data Interpretation3
2.1.Intravenous Administration of Drugs3
2.1.1.Utility of Intravenous Administration Studies3
2.1.2.General Considerations for Intravenous Administration Studies4
2.1.3.Sample Collection after Intravenous Administration4
2.2.Oral Administration of Drugs6
2.2.1.Utility of Oral Administration Studies6
2.2.2.General Considerations for Oral Administration Studies6
2.2.3.Sample Collection after Oral Administration--Blood7
2.3.Data Interpretation8
2.3.1.Compartmental Approach8
2.3.2.Noncompartmental Approach18
References28
3.New Approaches for High Throughput In Vivo Exposure Screening29
3.1.N-in-1 (Cassette or Cocktail) Dosing29
3.2.Postdose Pooling (or Cocktail Analysis)31
3.3.AUC Estimation from One Pooled Sample31
3.4.Continuous Sampling Method33
References33
4.Absorption35
4.1.Rate-Limiting Steps in Oral Drug Absorption35
4.1.1.Dissolution Rate-Limited Absorption35
4.1.2.Membrane Permeation Rate-Limited Absorption37
4.2.Factors Affecting Oral Absorption38
4.2.1.Physiological Factors38
4.2.2.Physiochemical Factors of Drugs40
4.2.3.Effects of pH and pK[subscript a] of a Drug on Absorption (pH-Partition Theory)41
4.2.4.Partition and Distribution Coefficients44
4.3.Bioavailability45
4.3.1.Definition45
4.3.2.Factors Affecting Bioavailability and the First-Pass Effect46
4.3.3.Estimating the Extent of Absorption47
4.3.4.Estimating the Rate of Absorption54
4.4.Enterohepatic Circulation66
4.4.1.Recognizing Enterohepatic Circulation67
4.4.2.Pharmacokinetic Implications of Enterohepatic Circulation68
4.4.3.Physicochemical Properties of Compounds for Biliary Excretion68
4.4.4.Measuring Clearance in the Presence of Enterohepatic Circulation68
4.4.5.Investigating Enterohepatic Circulation69
4.5.Fecal Excretion of Drugs and Coprophagy70
4.6.Lymphatic Absorption70
References71
5.Distribution73
5.1.Definition73
5.1.1.Proportionality Factor73
5.1.2.Pharmacokinetic Implications of the Volume of Distribution74
5.1.3.Summary of the Characteristics of the Volume of Distribution75
5.2.Different Volume Terms75
5.2.1.Apparent Volume of Distribution of the Central Compartment76
5.2.2.Volume of Distribution at Steady State76
5.2.3.Volume of Distribution at Pseudodistribution Equilibrium79
5.3.Estimating the Volume of Distribution80
5.3.1.Apparent Volume of the Central Compartment80
5.3.2.Volume of Distribution at Steady State80
5.3.3.Volume of Distribution at Pseudodistribution Equilibrium81
5.3.4.Differences among V[subscript c], V[subscript ss], and V[subscript [beta]81
5.3.5.Relationships among V[subscript c], V[subscript ss], V[subscript [beta], Cl[subscript s], and Cl[subscript d]82
References82
6.Clearance83
6.1.Definition83
6.1.1.Proportionality Factor83
6.1.2.Apparent Volume of Reference Fluid Cleared of a Drug per Unit Time83
6.2.Systemic (Plasma) Clearance85
6.2.1.Estimation85
6.2.2.Relationship between Systemic Clearance and the Volume of Distribution86
6.2.3.Relationship between Systemic Clearance and the Terminal Half-Life86
6.2.4.Amount of Drug Eliminated from the Body86
6.3.Organ Clearance87
6.3.1.Hepatic Clearance89
6.3.2.Biliary Clearance94
6.3.3.Renal Clearance95
6.4.Relationship between Systemic Blood and Organ Clearances98
6.5.Apparent Clearance following Oral Dosing99
6.6.Distributional Clearance99
6.7.Blood vs. Plasma Clearances100
6.7.1.Blood Clearance100
6.7.2.Plasma Clearance100
6.7.3.Relationship between Blood and Plasma Clearances100
6.7.4.Relationship between Blood and Plasma Concentrations101
6.7.5.Clearance Based on Unbound Drug Concentration in Plasma102
6.7.6.Relationship among Blood, Plasma, and Unbound Drug Clearances102
References103
7.Protein Binding105
7.1.Definition105
7.2.Estimating the Extent of Protein Binding107
7.2.1.Equilibrium Dialysis109
7.2.2.Ultrafiltration110
7.2.3.Microdialysis111
7.3.Pharmacokinetic and Pharmacodynamic Implications of Protein Binding112
7.3.1.Effects on Clearance112
7.3.2.Effects on the Volume of Distribution114
7.3.3.Effects on Half-Life115
7.3.4.Effects on Pharmacological Efficacy115
7.3.5.Effects on Drug-Drug Interaction115
7.4.Factors Affecting Protein Binding116
7.5.Nonlinearity of Plasma Protein Binding117
7.6.Plasma vs. Serum and In Vitro vs. Ex Vivo Protein Binding Measurements117
7.7.Protein Binding in Tissues118
7.7.1.General Trends in Drug Binding to (Muscle) Tissues118
7.7.2.Pharmacokinetic Implications of Tissue Binding119
7.8.Species Differences in Protein Binding119
References119
8.Metabolism121
8.1.Introduction121
8.1.1.Phase I Metabolism121
8.1.2.Phase II Metabolism122
8.1.3.Subcellular Locations of Metabolizing Enzymes123
8.2.Phase I Enzymes123
8.2.1.Cytochrome P450 Monooxygenase (Cytochrome P450, P450, or CYP)123
8.2.2.Flavin-Containing Monooxygenase (FMO)129
8.2.3.Esterase132
8.2.4.Alcohol Dehydrogenase (ADH)133
8.2.5.Aldehyde Dehydrogenase (ALDH)133
8.2.6.Monoamine Oxidase (MAO)134
8.3.Phase II Enzymes135
8.3.1.Uridine Diphosphate-Glucuronosyltransferase (UDPGT)135
8.3.2.Sulfotransferase (ST)137
8.3.3.N-Acetyltransferase (NAT)140
8.3.4.Glutathione S-Transferase (GST)141
8.3.5.Methyl Transferase142
8.3.6.Amino Acid Conjugation143
8.4.Extrahepatic Metabolism145
8.4.1.Intestinal Metabolism145
8.4.2.Renal Metabolism146
8.4.3.Metabolism in Blood146
8.5.Various Experiments for Drug Metabolism146
8.5.1.Examining Metabolic Profiles of Drugs146
8.5.2.Phenotyping of Cytochrome P450 Isoforms149
8.5.3.Important Factors in Drug Metabolism Experiments151
8.6.Physiological and Environmental Factors Affecting Drug Metabolism154
8.6.1.Physiological Factors154
8.6.2.Environmental Factors158
8.7.Metabolite Kinetics158
8.7.1."Formation-Rate-Limited" Metabolite Kinetics160
8.7.2."Elimination-Rate-Limited" Metabolite Kinetics161
8.7.3.Pharmacokinetic Properties of Metabolites162
8.7.4.Estimating Systemic Clearance of Metabolites162
8.8.Induction of Metabolism163
8.8.1.Mechanisms of Induction163
8.8.2.Characteristics of Induction164
8.8.3.Inducing Agents164
8.8.4.Time- and Dose-Dependence of Induction165
8.8.5.Species Differences in Induction165
References165
9.Biliary Excretion169
9.1.Relationship between Hepatic and Biliary Clearances169
9.2.Species Differences in Biliary Excretion169
9.3.Active Transporters for Biliary Excretion170
9.3.1.P-Glycoprotein171
9.3.2.Multidrug Resistance-Associated Protein171
References173
10.Nonlinear Pharmacokinetics175
10.1.Definitions175
10.1.1.Dose Dependency175
10.1.2.Time Dependency176
10.2.Michaelis-Menten Kinetics176
10.3.Pharmacokinetic Implications of Michaelis-Menten Kinetics177
10.3.1.First-Order Kinetics178
10.3.2.Zero-Order Kinetics178
10.3.3.Characteristics of Plasma Concentration-Time Profile of a Drug Subject to Michaelis-Menten Kinetics178
10.3.4.Estimating V[subscript max,app] and K[subscript m,app] from the Plasma Concentration-Time Profile In Vivo179
10.3.5.Systemic Clearance and Nonlinearity180
10.3.6.Effects of Nonlinearity on Pharmacokinetic Parameters181
10.3.7.Terminal Half-Life and Nonlinear Kinetics181
10.4.Factors Causing Nonlinear Pharmacokinetics182
10.5.Recognizing Nonlinear Pharmacokinetics185
10.6.Chronopharmacokinetics186
10.6.1.Absorption186
10.6.2.Distribution186
10.6.3.Metabolism187
10.6.4.Excretion187
10.7.Toxicokinetics187
References188
11.Pharmacodynamics and Pharmacokinetic/Pharmacodynamic Relationships189
11.1.Pharmacodynamics189
11.1.1.Definition189
11.1.2.Effect Site189
11.1.3.Pharmacological Effects190
11.1.4.Differences among Pharmacokinetics, the Pharmacokinetic/Pharmacodynamic Relationship, and Pharmacodynamics191
11.1.5.Important Factors in Pharmacodynamic Study Designs192
11.1.6.Effects of Protein Binding on Pharmacodynamics193
11.2.Pharmacodynamic Models193
11.2.1.Definition193
11.2.2.Implications of Pharmacodynamic Models193
11.2.3.Types of Pharmacodynamic Models194
11.2.4.Model Selection198
11.2.5.Difficulties in Pharmacodynamic Modeling198
11.3.Pharmacokinetic/Pharmacodynamic Modeling199
11.3.1.Definition199
11.3.2.Implications of Pharmacokinetic/Pharmacodynamic Modeling199
11.3.3.Types of Pharmacokinetic/Pharmacodynamic Models200
11.4.Proteresis or Hysteresis203
References204
12.Predicting Pharmacokinetics in Humans207
12.1.Allometry207
12.1.1.Definition207
12.1.2.Applications of Allometry for Predicting Pharmacokinetics in Humans207
12.2.Physiologically Based Approach211
12.2.1.Predicting Systemic Clearance of a Drug in Humans from In Vitro Data212
12.2.2.Predicting the Volume of Distribution of a Drug in Humans227
References228
13.Animal Physiology229
References238
Glossary241
Appendix273
A.Important Pharmacokinetic Equations273
B.Typical Pharmacokinetic Issues and Their Potential Causes278
C.References for Laboratory Animal Experiments279
D.Abbreviations282
Index287

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