Preface |
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xiii | |
DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION |
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1 | (198) |
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1. Drug Absorption, Distribution, Metabolism, and Excretion |
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3 | (8) |
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Different Approaches to Pharmacokinetics |
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4 | (5) |
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9 | (2) |
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11 | (8) |
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11 | (1) |
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12 | (5) |
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17 | (1) |
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17 | (2) |
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3. Parenteral Routes of Drug Administration |
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19 | (24) |
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Intraarterial Administration |
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20 | (1) |
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Intrathecal Administration |
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20 | (1) |
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Intravenous Administration |
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21 | (2) |
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Intramuscular Administration |
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23 | (1) |
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24 | (1) |
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Intranasal Administration |
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25 | (3) |
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28 | (3) |
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Transdermal Administration |
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31 | (6) |
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37 | (1) |
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38 | (1) |
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39 | (1) |
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40 | (3) |
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4. Enteral Routes of Drug Administration |
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43 | (20) |
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Physiology of the GI Tract |
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43 | (2) |
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GI Structure and Motility Factors |
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45 | (5) |
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Gastrointestinal Blood Flow in Relation to Drug Absorption |
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50 | (1) |
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Special Transport Mechanisms |
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51 | (1) |
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Animal Models for Oral Drug Absorption |
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52 | (7) |
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59 | (1) |
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60 | (3) |
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5. Factors Influencing Absorption and Bioavailability After Enteral Administration |
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63 | (12) |
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64 | (1) |
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65 | (1) |
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Hepatic Metabolism and the First-Pass Effect |
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66 | (3) |
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Enterohepatic Circulation |
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69 | (2) |
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Factors Influencing the First-Pass Effect |
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71 | (2) |
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73 | (1) |
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73 | (1) |
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73 | (2) |
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6. Physicochemical and Formulation Factors Affecting Drug Absorption |
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75 | (20) |
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75 | (1) |
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76 | (2) |
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78 | (2) |
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In Vitro-In Vivo Correlations |
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80 | (1) |
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81 | (1) |
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82 | (1) |
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Controlled-Release Formulations |
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82 | (7) |
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89 | (4) |
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93 | (1) |
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93 | (2) |
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7. Clinical Factors and Interactions Affecting Drug Absorption |
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95 | (24) |
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Influence of GI Disease on Drug Absorption |
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95 | (5) |
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Drug-Drug Interaction Affecting Absorption |
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100 | (5) |
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Drug-Food Interactions Affecting Absorption |
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105 | (11) |
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116 | (1) |
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116 | (1) |
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117 | (2) |
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119 | (26) |
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Distribution-Concentration Relationships |
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120 | (1) |
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121 | (1) |
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Perfusion and Diffusion Effects |
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122 | (2) |
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Binding of Drugs to Tissues |
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124 | (4) |
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Intravascular and Extravascular Drug Binding |
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128 | (7) |
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Penetration of Drug into the Central Nervous System |
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135 | (4) |
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Methods of Determining Drug Distribution |
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139 | (2) |
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141 | (1) |
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142 | (1) |
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142 | (3) |
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145 | (18) |
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145 | (2) |
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Mechanisms of Drug Metabolism |
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147 | (9) |
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Species, Sex, and Age Differences |
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156 | (3) |
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159 | (1) |
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159 | (1) |
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160 | (1) |
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160 | (1) |
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161 | (2) |
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10. Effect of Liver Disease on Drug Metabolism and Pharmacokinetics |
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163 | (12) |
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Function and Structure of the Liver |
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164 | (1) |
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Types and Severity of Liver Disease |
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164 | (1) |
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Effects on Pharmacodynamics and Pharmacokinetics |
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165 | (4) |
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Examples of Effects of Liver Disease on the Pharmacokinetics of Some Drug Classes |
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169 | (2) |
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171 | (1) |
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172 | (1) |
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172 | (3) |
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175 | (12) |
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Structure and Function of the Kidney |
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175 | (3) |
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178 | (1) |
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Renal Clearance and Plasma Clearance |
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179 | (3) |
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Relationship Among Clearance, Drug Elimination Rate, and Half-Life |
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182 | (2) |
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184 | (1) |
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184 | (1) |
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185 | (2) |
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12. Drug Elimination in Renal Impairment |
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187 | (12) |
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Methods of Measuring Renal Function |
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188 | (2) |
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Use of Creatinine Clearance to Predict the Effect of Renal Impairment on Drug Elimination |
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190 | (1) |
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Methods of Dosage Adjustment |
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191 | (3) |
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Maintenance of Patients with End-Stage Kidney Disease |
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194 | (1) |
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195 | (1) |
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196 | (1) |
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197 | (2) |
THE MATHEMATICS OF PHARMACOKINETICS |
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199 | (124) |
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13. The One-Compartment Open Model with Intravenous Dosage |
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201 | (22) |
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The One-Compartment Open Model with Bolus Intravenous Injection |
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202 | (5) |
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207 | (3) |
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Urinary Excretion Kinetics |
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210 | (1) |
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Construction of Sigma-Minus Plots |
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211 | (2) |
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Zero-Order Drug Input and First-Order Elimination |
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213 | (6) |
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219 | (1) |
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219 | (2) |
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221 | (2) |
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14. The One-Compartment Open Model with First-Order Absorption and Elimination |
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223 | (22) |
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General Aspects of First-Order Absorption and Elimination |
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223 | (3) |
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Graphical Estimation of Parameters |
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226 | (4) |
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Other Parameters Associated with First-Order Absorption and Elimination |
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230 | (2) |
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232 | (2) |
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Area Under the Drug-Concentration Curve (AUC) |
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234 | (2) |
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236 | (1) |
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Cumulative Urinary Excretion of Unchanged Drug |
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237 | (4) |
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241 | (1) |
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242 | (1) |
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243 | (2) |
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15. Multiple-Dose Kinetics |
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245 | (14) |
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Drug Accumulation with Repeated Doses |
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245 | (5) |
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250 | (2) |
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The Degree of Drug Accumulation with Repeated Dosing and the Loading Dose Required To Instantaneously Achieve Steady-State Levels |
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252 | (1) |
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First-Order Absorption Case |
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253 | (3) |
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256 | (1) |
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256 | (1) |
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257 | (2) |
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16. Metabolite Pharmacokinetics |
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259 | (12) |
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Pharmacokinetics of Metabolite Formation and Elimination |
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259 | (3) |
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Analysis of Metabolite Concentrations in Plasma, and Urinary Excretion |
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262 | (3) |
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Resolving the Pharmacokinetics of Metabolite and Parent Drug |
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265 | (3) |
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268 | (1) |
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268 | (1) |
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269 | (2) |
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17. The Two-Compartment Open Model with Intravenous or Oral Administration |
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271 | (26) |
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The Two-Compartment Model with Bolus Intravenous Injection |
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272 | (1) |
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Interpretation of Drug-Concentration Profiles in Plasma To Obtain Parameter Estimates |
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273 | (3) |
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Graphical Estimation of Kinetic Parameters |
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276 | (2) |
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Derivation of AUC(0XXX), Plasma Clearance, and Renal Clearance |
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278 | (1) |
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Volume of Distribution at Equilibrium |
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279 | (3) |
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Kinetics of Tissue Distribution |
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282 | (1) |
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Obtaining Parameter Estimates from Urinary Excretion Data |
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283 | (2) |
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The Two-Compartment Model with First-Order Drug Input |
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285 | (3) |
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Drug Concentration in the First Compartment |
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288 | (4) |
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Some Model-Independent Parameters for a Drug that Obeys Two-Compartment Model Kinetics |
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292 | (2) |
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294 | (1) |
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295 | (1) |
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295 | (2) |
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18. Physiological Pharmacokinetic Models |
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297 | (14) |
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Description of Physiological Pharmacokinetic Model |
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297 | (2) |
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299 | (1) |
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Blood Flow Rate-Limited Transport |
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300 | (5) |
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Membrane-Limited Transport |
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305 | (1) |
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Experimental Considerations |
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306 | (2) |
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308 | (1) |
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309 | (1) |
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309 | (2) |
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19. Nonlinear Pharmacokinetics |
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311 | (12) |
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311 | (2) |
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Expressions Useful in Elimination Kinetics |
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313 | (3) |
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Obtaining Estimates of V(m) and K(m) from Plasma-Level Data |
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316 | (2) |
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Influence of Saturable Kinetics on Drug Elimination, Area Under the Drug-Concentration Curve, and First-Pass Effect |
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318 | (3) |
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321 | (1) |
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321 | (1) |
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322 | (1) |
APPLICATIONS OF PHARMACOKINETICS IN DRUG DISCOVERY AND DEVELOPMENT |
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323 | (32) |
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20. Pharmacokinetics and Toxicokinetics |
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325 | (6) |
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Pharmacokinetics and Pharmacodynamics |
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325 | (1) |
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Toxicokinetics and Toxicodynamics |
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326 | (1) |
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Technical Differences Between Pharmacokinetics and Toxicokinetics |
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326 | (2) |
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Philosophical Differences Between Pharmacokinetics and Toxicokinetics |
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328 | (1) |
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329 | (1) |
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329 | (1) |
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329 | (2) |
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21. Role of Pharmacokinetics in Drug Discovery and Development |
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331 | (12) |
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331 | (1) |
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Drug Discovery and Development |
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332 | (8) |
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Regulatory Submissions and Drug Labeling |
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340 | (1) |
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Postsubmission and Postmarketing Studies |
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341 | (1) |
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341 | (1) |
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342 | (1) |
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342 | (1) |
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22. Integration of Pharmacokinetics into Research and Development |
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343 | (12) |
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343 | (1) |
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344 | (1) |
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344 | (1) |
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Comparison of the Alternatives |
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345 | (5) |
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350 | (2) |
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352 | (1) |
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353 | (2) |
APPENDIXES |
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355 | (26) |
Appendix I: Computer Methods and Software for Pharmacokinetic Data Analysis |
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357 | (2) |
Appendix II: Worked Answers to Problem Sets |
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359 | (14) |
Appendix III: Nomenclature |
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373 | (4) |
Appendix IV: Glossary |
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377 | (4) |
INDEX |
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381 | |