Pharmacokinetics. Processes, Mathematics, and Applications. Second Edition. Peter G. Welling. Institut de Recherche Jouveinal

Transcription

1 Pharmacokinetics Processes, Mathematics, and Applications Second Edition Peter G. Welling Institut de Recherche Jouveinal ACS Professional Reference Book American Chemical Society Washington, DC

2 Contents Preface xiii DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION 1 1. Drug Absorption, Distribution, Metabolism, and Excretion 3 Different Approaches to Pharmacokinetics / 4 References / 9 2. Drug Transport 11 The Cell Membrane / 11 Membrane Transport / 12 Summary / 17 References / Parenteral Routes of Drug Administration 19 Intraarterial Administration / 20 Intrathecal Administration / 20 Intravenous Administration / 21 Intramuscular Administration / 23 Buccal Administration / 24 Intranasal Administration / 25 Inhalation / 28 Transdermal Administration / 31 Vaginal Administration / 37 Rectal Administration / 38 Summary / 39 References / 40 VII

3 S: PROCESSES, MATHEMATICS, AND APPLICATIONS! 4. Enteral Routes of Drug Administration 43 Physiology of the GI Tract / 43 GI Structure and Motility Factors / 45 Gastrointestinal Blood Flow in Relation to Drug Absorption / 50 Special Transport Mechanisms / 51 Animal Models for Oral Drug Absorption / 52 Summary / 59 References / Factors Influencing Absorption and Bioavailability After Enteral Administration 63 Metabolism in the Gut / 64 Metabolism in the Lung / 65 Hepatic Metabolism and the First-Pass Effect / 66 Enterohepatic Circulation / 69 Factors Influencing the First-Pass Effect / 71 Summary / 73 Problems / 73 References / Physicochemical and Formulation Factors Affecting Drug Absorption 75 Chemical Factors / 75 Physical Factors / 76 Formulation Factors / 78 In Vitro-In Vivo Correlations / 80 Excipients / 81 Coated Tablets / 82 Controlled-Release Formulations / 82 Absorption Enhancers / 89 Summary / 93 References / Clinical Factors and Interactions Affecting Drug Absorption 95 Influence of GI Disease on Drug Absorption / 95 Drug-Drug Interactions Affecting Absorption / 100 Drug-Food Interactions Affecting Absorption / 105 Conclusions / 116 Summary / 116 References / Drug Distribution 119 Distribution-Concentration Relationships / 120 Capillary Permeability / 121 Perfusion and Diffusion Effects / 122 Binding of Drugs to Tissues / 124

4 Intravascular and Extravascular Drug Binding / 128 Penetration of Drug into the Central Nervous System / 135 Methods of Determining Drug Distribution / 139 Summary / 141 Problems / 142 References / Drug Metabolism 145 Sites of Drug Metabolism / 145 Mechanisms of Drug Metabolism / 147 Species, Sex, and Age Differences / 156 Steric Factors / 159 Enzyme Induction / 159 Enzyme Inhibition / 160 Summary / 160 References / Effect of Liver Disease on Drug Metabolism and Pharmacokinetics 163 Function and Structure of the Liver / 164 Types and Severity of Liver Disease / 164 Effects on Pharmacodynamics and Pharmacokinetics / 165 Examples of Effects of Liver Disease on the Pharmacokinetics of Some Drug Classes / 169 Conclusions / 171 Summary / 172 References / Renal Excretion 175 Structure and Function of the Kidney / 175 Clearance / 178 Renal Clearance and Plasma Clearance / 179 Relationship Among Clearance, Drug Elimination Rate, and Half-Life / 182 Summary / 184 Problems / 184 References / Drug Elimination in Renal Impairment 187 Methods of Measuring Renal Function / 188 Use of Creatinine Clearance to Predict the Effect of Renal Impairment on Drug Elimination / 190 Methods of Dosage Adjustment / 191 Maintenance of Patients with End-Stage Kidney Disease / 194 Summary / 195 Problems / 196 References / 197

5 THE MATHEMATICS OF PHARMACOKINETICS The One-Compartment Open Model with Intravenous Dosage 201 The One-Compartment Open Model with Bolus Intravenous Injection / 202 The Trapezoidal Rule / 207 Urinary Excretion Kinetics / 210 Construction of Sigma-Minus Plots / 211 Zero-Order Drug Input and First-Order Elimination / 213 Summary / 219 Problems / 219 References / The One-Compartment Open Model with First-Order Absorption and Elimination 223 General Aspects of First-Order Absorption and Elimination / 223 Graphical Estimation of Parameters / 226 Other Parameters Associated with First-Order Absorption and Elimination / 230 Drug Absorption Plots / 232 Area Under the Drug-Concentration Curve jauc) / 234 Absorption Lag Time / 236 Cumulative Urinary Excretion of Unchanged Drug / 237 Summary / 241 Problems / 242 References / Multiple-Dose Kinetics 245 Drug Accumulation with Repeated Doses / 245 Drug Accumulation Rate / 250 The Degree of Drug Accumulation with Repeated Dosing and the Loading Dose Required To Instantaneously Achieve Steady-State Levels / 252 First-Order Absorption Case / 253 Summary / 256 Problems / 256 References / Metabolite Pharmacokinetics 259 Pharmacokinetics of Metabolite Formation and Elimination / 259 Analysis of Metabolite Concentrations in Plasma, and Urinary Excretion / 262 Resolving the Pharmacokinetics of Metabolite and Parent Drug / 265 Summary / 268 Problems / 268 References / 269

6 17. The Two-Compartment Open Model with Intravenous or Oral Administration 271 The Two-Compartment Model with Bolus Intravenous Injection / 272 Interpretation of Drug-Concentration Profiles in Plasma To Obtain Parameter Estimates / 273 Graphical Estimation of Kinetic Parameters / 276 Derivation of AUC ^~, Plasma Clearance, and Renal Clearance / 278 Volume of Distribution at Equilibrium / 279 Kinetics of Tissue Distribution / 282 Obtaining Parameter Estimates from Urinary Excretion Data / 283 The Two-Compartment Model with First-Order Drug Input / 285 Drug Concentration in the First Compartment / 288 Some Model-Independent Parameters for a Drug that Obeys Two-Compartment Model Kinetics / 292 Summary / 294 Problems / 295 References / Physiological Pharmacokinetic Models 297 Description of Physiological Pharmacokinetic Model / 297 Organ Clearance / 299 Blood Flow Rate-Limited Transport / 300 Membrane-Limited Transport / 305 Experimental Considerations / 306 Summary / 308 Problems / 309 References / Nonlinear Pharmacokinetics 311 Saturable Processes / 311 Expressions Useful in Elimination Kinetics / 313 Obtaining Estimates of V m and K m from Plasma-Level Data / 316 Influence of Saturable Kinetics on Drug Elimination, Area Under the Drug-Concentration Curve, and First-Pass Effect / 318 Summary / 321 Problems / 321 References / 322 APPLICATIONS OF PHARMACOKINETICS IN DRUG DISCOVERY AND DEVELOPMENT Pharmacokinetics and Toxicokinetics 325 Pharmacokinetics and Pharmacodynamics / 325 Toxicokinetics and Toxicodynamics / 326 Technical Differences Between Pharmacokinetics and Toxicokinetics / 326

7 PH \RMACOkl\ETK V PRO< FSSCS, MATHEMATICS. AND APPLIC ATIONS Philosophical Differences Between Pharmacokinetics and Toxicokinetics / 328 Conclusions / 329 Summary / 329 References / Role of Pharmacokinetics in Drug Discovery and Development 331 Regulatory Submissions / 331 Drug Discovery and Development / 332 Regulatory Submissions and Drug Labeling / 340 Postsubmission and Postmarketing Studies / 341 Conclusions / 341 Summary / 342 References / Integration of Pharmacokinetics into Research and Development 343 The R&D Sequence / 343 Statement of the Problem / 344 The Alternatives / 344 Comparison of the Alternatives / 345 Conclusions / 350 Summary / 352 Reference / 353 APPENDIXES 355 Appendix I: Computer Methods and Software for Pharmacokinetic Data Analysis 357 Appendix II: Worked Answers to Problem Sets 359 Appendix III: Nomenclature 373 Appendix IV: Glossary 377 INDEX 381