Models for Assessing Drug Absorption and MetabolismRonald T. Borchardt, Philip L. Smith, Glynn Wilson Pharmaceutical scientists in industry and academia will appreciate this single reference for its detailed experimental procedures for conducting biopharmaceutical studies. This well-illustrated guide allows them to establish, validate, and implement commonly used in situ and in vitro model systems. Chapters provide ready access to these methodologies for studies of the intestinal, buccal, nasal and respiratory, vaginal, ocular, and dermal epithelium as well as the endothelial and elimination barriers. |
Contents
General Principles in the Characterization and Use of Model Systems for Biopharmaceutical Studies | 1 |
2 BIOLOGICAL BARRIERS TO DRUG DELIVERY | 3 |
3 DESIRABLE CHARACTERISTICS OF A MODEL SYSTEM | 4 |
4 CHARACTERIZATION OF MODEL SYSTEMS | 5 |
5 APPLICATIONS TO PHARMACEUTICAL PROBLEMS | 7 |
6 FUTURE DIRECTIONS | 8 |
7 CONCLUSIONS | 9 |
Methods for Evaluating Intestinal Permeability and Metabolism in Vitro | 13 |
33 Mathematical Model | 228 |
34 Estimation of Capillary Permeability | 230 |
Kinetic Analysis of the Renal Tubular Secretion of Organic Anions and Cations by the MID Method Combined with a Mathematical Model | 231 |
4 ADVANTAGES AND DISADVANTAGES OF THE IPK | 233 |
REFERENCES | 236 |
Brain Microvessel Endothelial Cell Culture Systems | 239 |
2 METHODS | 240 |
23 Brain Microvessel Isolation | 241 |
2 METHODS | 14 |
22 Tissue Preparation | 17 |
23 Transport Studies | 19 |
24 Metabolism Studies | 21 |
3 APPLICATIONS FOR ABSORPTION AND METABOLISM | 22 |
32 Evaluation of Formulation Approaches | 24 |
33 Metabolism Studies | 27 |
34 Discovery Screening | 28 |
4 ADVANTAGES AND DISADVANTAGES OF TISSUE TECHNIQUES | 29 |
REFERENCES | 30 |
Cultured Intestinal Epithelial Cell Models | 35 |
2 METHODS | 36 |
23 Experimental Protocols | 39 |
24 Calculations of Data | 42 |
3 APPLICATIONS TO ABSORPTION AND METABOLISM STUDIES | 45 |
32 Drug Metabolism | 46 |
33 In Vitroin Vivo Correlations | 47 |
4 ADVANTAGES AND DISADVANTAGES OVER OTHER METHODS | 48 |
REFERENCES | 49 |
Intestinal Rings and Isolated Intestinal Mucosal Cells | 51 |
2 PREPARATION OF EVERTED RINGS OR ISOLATED EPITHELIAL CELLS | 52 |
3 DEMONSTRATION OF FUNCTIONAL VIABILITY OF RINGS AND CELLS | 56 |
4 EXPERIMENTAL TECHNIQUES FOR DRUG ABSORPTION MEASUREMENTS | 57 |
41 Intestinal Rings | 58 |
42 Isolated Intestinal Mucosal Cells | 61 |
5 ADVANTAGES LIMITATIONS AND POTENTIAL APPLICATIONS OF RINGS AND CELLS IN QUANTITATING DRUG TRANSPORT | 63 |
REFERENCES | 64 |
Models of Drug Absorption in Situ and in Conscious Animals | 67 |
2 IN SITU ABSORPTION MODELS | 68 |
22 Cannulation of the Lumen with Blood Replacement | 69 |
24 Simultaneous Perfusion of the Rat Small Intestine and Liver | 71 |
3 ABSORPTION ASSESSMENT IN CONSCIOUS ANIMALS | 73 |
31 Surgical Techniques | 74 |
32 DATA ANALYSIS IN IN VIVO EXPERIMENTS | 81 |
4 COMPARISON OF METHODS USED TO STUDY GASTROINTESTINAL ABSORPTION | 82 |
Model Systems for Intestinal Lymphatic Transport Studies | 85 |
2 METHODS | 86 |
22 Animal Handling and Preparation | 87 |
23 Surgical Procedures | 88 |
24 General Experimental Protocol and Animal Monitoring | 92 |
26 Drug and TViglyceride Analysis | 94 |
27 Alternative Animal Models | 96 |
3 METHODOLOGICAL DIFFERENCES IN TRANSPORT STUDIES | 97 |
33 Anesthetized versus Conscious Models | 98 |
34 Choice of Coadministered Lipid | 99 |
35 Scaling Rat Lymphatic Transport Data to Higher Species | 100 |
REFERENCES | 101 |
Buccal Tissues and Cell Culture | 103 |
2 METHODS | 104 |
22 Buccal Cell Culture | 107 |
23 In Vivo Dog Model | 109 |
3 APPLICATIONS TO ABSORPTION AND METABOLISM | 110 |
4 ADVANTAGES AND DISADVANTAGES COMPARED TO OTHER METHODS | 111 |
REFERENCES | 112 |
Isolated Hepatocytes | 115 |
2 METHODS | 116 |
23 Calculations of Data | 117 |
24 Comments | 118 |
3 ADVANTAGES AND DISADVANTAGES OVER OTHER METHODS | 119 |
Cultured Rat Hepatocytes | 121 |
2 METHODS | 122 |
22 Hepatocyte Isolation and Primary Cell Culture | 125 |
23 Overlay of Cell Cultures with Extracellular Matrix | 127 |
3 PROPERTIES OF PRIMARY CULTURES OF RAT HEPATOCYTES | 128 |
34 Use of Hepatocyte Cultures for in Vitro Studies | 129 |
42 Matrix Effects | 134 |
5 APPLICATIONS TO DRUG DEVELOPMENT AND METABOLISM | 135 |
52 Microsomal Enzyme Induction | 139 |
53 Drug Metabolism | 143 |
6 ADVANTAGES AND DISADVANTAGES OF CULTURED HEPATOCYTES | 144 |
7 APPENDIX | 146 |
72 Procedures for Hepatocyte Isolation | 148 |
REFERENCES | 152 |
Isolated Perfused Liver | 161 |
2 METHODS | 163 |
22 Perfusate Composition and Flow Rate | 167 |
23 Surgical Procedures | 169 |
24 Viability Assessments | 173 |
25 Experimental Protocols and Data Collection and Analysis | 176 |
26 Comparison of Techniques | 178 |
3 APPLICATIONS OF THE ISOLATED PERFUSED LIVER | 179 |
32 Specialized Applications | 182 |
4 ADVANTAGES AND DISADVANTAGES OF THE ISOLATED PERFUSED LIVER AS COMPARED TO OTHER MODELS | 183 |
REFERENCES | 186 |
Isolated Renal Brush Border and Basolateral Membrane Vesicles and Cultured Renal Cells | 193 |
2 ISOLATED RENAL PLASMA MEMBRANE VESICLES | 194 |
22 Materials | 195 |
23 Procedures | 196 |
3 CULTURED RENAL EPITHELIAL CELLS | 201 |
32 Materials | 202 |
4 TRANSPORT STUDIES IN MEMBRANE VESICLES AND CELLS | 205 |
42 Driving Force Studies | 206 |
43 Inhibition Studies | 207 |
44 Counterflux and Transstimulation Studies | 208 |
REFERENCES | 209 |
Use of an Isolated Perfused Kidney to Assess Renal Clearance of Drugs Information Obtained in SteadyState and NonSteadyState Experimental Syste... | 211 |
2 ISOLATED PERFUSED KIDNEY | 212 |
22 Hemodynamic Properties and Viability of the IPK | 214 |
24 Assessment of Renal Clearance in the IPK | 215 |
26 The NonFiltering Perfused Kidney System | 220 |
Analysis of Renal Handling of Epidermal Growth Factor Using the FK and NFK | 221 |
3 MULTIPLE INDICATOR DILUTION METHOD | 224 |
31 PulseInjection MID Method Using the Rat IPK | 225 |
24 Preparation of Growth Surfaces for Brain Microvessels | 245 |
25 Seeding of Brain Microvessels onto Growth Surfaces | 246 |
3 EXPERIMENTAL PROTOCOLS FOR UPTAKE AND TRANSPORT STUDIES | 248 |
33 Protein Estimation | 249 |
4 CALCULATIONS OF DATA | 250 |
5 PHARMACEUTICAL APPLICATIONS | 251 |
53 Permeability Regulation | 252 |
62 Appropriate Roles and Relationship to the BBB in Vivo | 253 |
64 Status of Cell Line Development | 254 |
7 CONCLUSIONS AND FUTURE PERSPECTIVES | 255 |
Methods to Study Drug Transport in Isolated Choroid Plexus Tissue and Cultured Cells | 259 |
12 Importance of the Choroid Plexus in Drug Delivery and Targeting to the Brain | 261 |
14 Techniques for the Study of Drug Transport in the Choroid Plexus | 262 |
21 Materials | 263 |
22 Procedures | 264 |
23 Mechanisms of Transport | 266 |
24 Potential Problems | 271 |
25 Calculation of Transport Parameters | 272 |
3 CULTURED CHOROID PLEXUS EPITHELIAL CELLS | 273 |
31 Materials | 274 |
32 Procedures | 275 |
33 Calculation of Transport Parameters and Flux | 281 |
REFERENCES | 282 |
Brain Perfusion Systems for Studies of Drug Uptake and Metabolism in the Central Nervous System | 285 |
2 IN SITU BRAIN PERFUSION METHOD | 287 |
22 Surgical Preparation | 288 |
23 Perfusion Fluid | 291 |
24 Perfusion Apparatus | 293 |
25 Perfusion Experiment | 295 |
26 Calculations | 296 |
3 APPLICATIONS | 299 |
4 ADVANTAGES AND DISADVANTAGES | 302 |
REFERENCES | 303 |
In Vitro Nasal Models | 309 |
2 METHODS | 310 |
23 Isolated Airway Epithelial Membranes | 314 |
24 Nasal Homogenate Systems | 317 |
3 ABSORPTION AND METABOLISM APPLICATIONS | 319 |
4 ADVANTAGES AND DISADVANTAGES OF IN VITRO NASAL MODELS | 320 |
REFERENCES | 321 |
Models for Investigation of Peptide and Protein Transport across Cultured Mammalian Respiratory Epithelial Barriers | 325 |
2 METHODS AND MATERIALS | 326 |
21 Primary Culture of Alveolar Epithelial Cells | 327 |
22 Primary Culture of Airway Epithelial Cells | 330 |
3 AIRINTERFACE CULTURE | 333 |
42 Flux Measurements of Peptides and Proteins | 335 |
43 Metabolism of Peptides and Proteins | 336 |
REFERENCES | 339 |
Drug Transport across Xenopus Alveolar Epithelium in Vitro | 347 |
2 METHODS | 348 |
23 Electrical Parameters | 349 |
25 Electron Microscopy | 350 |
3 EXPERIMENTAL PROTOCOLS | 351 |
33 Determination of TissueAssociated Radioactivity | 352 |
34 Calculation of Data | 353 |
5 ADVANTAGES AND DISADVANTAGES OVER OTHER METHODS | 356 |
REFERENCES | 358 |
In Situ and in Vivo Methods for Pulmonary Delivery | 361 |
2 ISOLATED PERFUSED RAT LUNG MODEL IPRL | 362 |
22 Materials and Methods | 363 |
23 Treatment of the Data | 364 |
32 Materials and Methods | 365 |
33 Treatment of the Data | 366 |
4 AEROSOL DEPOSITION MODEL | 367 |
42 Materials and Methods | 368 |
43 Treatment of the Data | 369 |
5 DISCUSSION | 371 |
373 | |
In Vitro Viable Skin Model | 375 |
2 METHODS | 376 |
22 Preparation of Membrane | 377 |
23 Diffusion Cell Design | 378 |
24 Receptor Fluid | 380 |
25 Temperature | 381 |
29 Measurement of Percutaneous Absorption | 382 |
4 COMPARISON OF MODEL TO OTHER METHODS | 385 |
Isolated Perfused Porcine Skin Flap Systems | 387 |
2 METHODS | 388 |
22 Isolated Perfusion Technique | 390 |
24 Design of Percutaneous Absorption and Transdermal Drug Delivery Studies | 391 |
25 Data Analysis | 392 |
26 Pharmacokinetic Modeling and in Vitro to in Vivo Extrapolation | 395 |
3 APPLICATIONS | 398 |
32 Iontophoresis | 402 |
4 ADVANTAGES AND DISADVANTAGES OF THE IPPSF | 404 |
405 | |
Vaginal Epithelial Models | 409 |
21 Materials | 411 |
23 In Situ Model | 414 |
24 In Vivo Model | 418 |
25 Ovariectomized Rat Model | 419 |
26 Metabolic Enzyme Activity Study | 420 |
3 APPLICATIONS | 421 |
4 ADVANTAGES AND DISADVANTAGES | 422 |
423 | |
Ocular Epithelial Models | 425 |
2 CHOICE OF ANIMAL MODELS | 426 |
3 TYPES OF EXPERIMENTAL MODELS | 427 |
32 In Vivo Models | 428 |
4 CONCLUSIONS | 432 |
433 | |
437 | |
Other editions - View all
Models for Assessing Drug Absorption and Metabolism Ronald T. Borchardt,Philip L. Smith,Glynn Wilson No preview available - 2013 |
Models for Assessing Drug Absorption and Metabolism Ronald T. Borchardt,Philip L. Smith,Glynn Wilson No preview available - 2014 |
Common terms and phrases
activity amino acid anesthetized animal apical artery assess Audus basolateral bile bioavailability Biochem Biol blood blood-brain barrier BMECS Borchardt bovine brush border buffer Caco-2 cells cannula cell culture cell monolayers centrifuged Chikhale choroid plexus cimetidine clearance collagen compound concentration cytochrome determined diffusion dose drug absorption drug delivery drug transport effects endothelial cells enzymes epithelial cells epithelium experimental extracellular filter fluid flux function hepatic hepatocyte cultures hepatocytes incubation inhibitor IPPSF isolated perfused rat kidney kinetics lipid liver lung lymphatic transport mannitol measured medium mesenteric method molecules monolayers mucosa nasal oxygen pellet peptide perfused liver perfused rat liver perfusion permeability Pharm pharmaceutical pharmacokinetic Pharmacol phenobarbital Physiol plasma preparation primary cultures procedure protein rabbit radiolabeled rat hepatocytes renal samples serum skin small intestine Smith substrate surface Takasato technique tissue tracheal transepithelial tubing uptake Ussing chambers vaginal vascular vein viability vitro vivo
References to this book
Oral Drug Absorption: Prediction and Assessment Jennifer B. Dressman,Hans Lennernas No preview available - 2000 |