Pharmacokinetics Processes, Mathematics, and Applications Second Edition Peter G. Welling Institut de Recherche Jouveinal ACS Professional Reference Book American Chemical Society Washington, DC
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 / 17 3. 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
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 / 60 5. 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 / 73 6. 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 / 93 7. 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 / 117 8. Drug Distribution 119 Distribution-Concentration Relationships / 120 Capillary Permeability / 121 Perfusion and Diffusion Effects / 122 Binding of Drugs to Tissues / 124
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 / 142 9. 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 / 161 10. 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 / 172 11. 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 / 185 12. 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
THE MATHEMATICS OF PHARMACOKINETICS 199 13. 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 / 221 14. 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 / 243 15. 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 / 257 16. 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
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 / 295 18. 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 / 309 19. 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 323 20. Pharmacokinetics and Toxicokinetics 325 Pharmacokinetics and Pharmacodynamics / 325 Toxicokinetics and Toxicodynamics / 326 Technical Differences Between Pharmacokinetics and Toxicokinetics / 326
PH \RMACOkl\ETK V PRO< FSSCS, MATHEMATICS. AND APPLIC ATIONS Philosophical Differences Between Pharmacokinetics and Toxicokinetics / 328 Conclusions / 329 Summary / 329 References / 329 21. 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 / 342 22. 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