Prodrugs and targeted delivery: towards better ADME properties
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2011
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| Schriftenreihe: | Methods and principles in medicinal chemistry
47 |
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| Beschreibung: | XXIV, 496 S. Ill., graph. Darst. |
| ISBN: | 9783527326037 |
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IMAGE 1
CONTENTS
LIST OF CONTRIBUTORS XVII PREFACE XXI A PERSONAL FOREWORD XXIII
PART ONE PRODRUG DESIGN AND INTELLECTUAL PROPERTY 1
1 PRODRUG STRATEGIES IN DRUG DESIGN 3 JARKKO RAUTIO 1.1 PRODRUG CONCEPT
3
1.2 BASICS OF PRODRUG DESIGN 4
1.3 RATIONALE FOR PRODRUG DESIGN 5
1.3.1 OVERCOMING FORMULATION AND ADMINISTRATION PROBLEMS 6 1.3.2
OVERCOMING ABSORPTION BARRIERS 8 1.3.3 OVERCOMING DISTRIBUTION PROBLEMS
9 1.3.4 OVERCOMING METABOLISM AND EXCRETION PROBLEMS 10
1.3.5 OVERCOMING TOXICITY PROBLEMS 10 1.3.6 LIFE CYCLE MANAGEMENT 13 1.4
HISTORY OF PRODRUG DESIGN 14
1.5 RECENTLY MARKETED PRODRUGS 17 1.5.1 PRODRUG PREVALENCE 17 1.5.2
RECENT PRODRUG APPROVALS 17 1.6 CONCLUDING REMARKS 25
REFERENCES 26
2 THE MOLECULAR DESIGN OF PRODRUGS BY FUNCTIONAL GROUP 31 VICTOR R.
CUARINO 2.1 INTRODUCTION 31
2.2 THE PRODRUG CONCEPT AND BASICS OF DESIGN 32 2.3 COMMON FUNCTIONAL
GROUP APPROACHES IN PRODRUG DESIGN 34
PRODRUGS AND TARGETED DELIVERY: TOWARDS BETTER ADME PROPERTIES. EDITED
BY JARKKO RAUTIO COPYRIGHT 2011 WILEY-VCH VERLAG GMBH & CO. KGAA,
WEINHEIM ' ISBN: 978-3-527-32603-7
BIBLIOGRAFISCHE INFORMATIONEN HTTP://D-NB.INFO/1004024096
DIGITALISIERT DURCH
IMAGE 2
VI CONTENTS
2.3.1 ALIPHATIC AND AROMATIC ALCOHOLS 34
2.3.1.1 PHOSPHATE MONOESTERS 35 2.3.1.2 SIMPLE ACYL ESTERS 37 2.3.1.3
AMINO ACID ESTERS 38 2.3.1.4 OTHER ESTER-BASED APPROACHES 39 2.3.2
CARBOXYLIC ACIDS 40
2.3.2.1 ALKYL ESTERS 41 2.3.2.2 AMINOALKYL ESTERS 42 2.3.2.3 SPACER
GROUPS TO ALLEVIATE STERIC HINDRANCE 42 2.3.3 IMIDES, AMIDES, AND OTHER
NH ACIDS 43 2.3.3.1 IMIDE-TYPE NH ACIDS 44 2.3.3.2 AMIDE-TYPE NH ACIDS
44 2.3.3.3 SULFONAMIDE NH ACIDS 48 2.3.4 PHOSPHATES, PHOSPHONATES, AND
PHOSPHINATES 49 2.3.4.1 SIMPLE ALKYL AND ARYL ESTERS 49 2.3.4.2
ACYLOXYALKYL AND ALKOXYCARBONYLOXYALKYL ESTERS 50 2.3.4.3 ARYL
PHOSPHO(N/R)AMIDATES AND PHOSPHO(N/R)DIAMIDES 51 2.3.4.4 HEPDIRECT
TECHNOLOGY 53 2.3.5 AMINES AND BENZAMIDINES 53 2.3.5.1
N-ACYLOXYALKOXYCARBONYL PRODRUGS 54 2.3.5.2 N-MANNICH BASES 55 2.3.5.3
AF-ACYLOXYALKYL AND N-PHOSPHORYLOXYALKYL PRODRUGS OF TERTIARY
AMINES 55
2.3.5.4 N-HYDROXY AND OTHER MODIFICATIONS FOR BENZAMIDINES 56 2.4
CONCLUSIONS 56
REFERENCES 57
3 INTELLECTUAL PROPERTY PRIMER ON PHARMACEUTICAL PATENTS WITH A SPECIAL
EMPHASIS ON PRODRUGS AND METABOLITES 61 EYAL H. BARASH 3.1 INTRODUCTION
61
3.2 PATENTS AND FDA APPROVAL PROCESS 61 3.3 OBTAINING A PATENT 65
3.3.1 UTILITY 66
3.3.2 NOVELTY 67
3.3.3 NONOBVIOUSNESS 71
3.4 CONCLUSION 78
PART TWO PRODRUGS ADDRESSING ADMET ISSUES 79
4 INCREASING LIPOPHILICITY FOR ORAL DRUG DELIVERY 81 MAJID Y. MORIDANI
4.1 INTRODUCTION 81
4.2 PK A , DEGREE OF IONIZATION, PARTITION COEFFICIENT, AND DISTRIBUTION
COEFFICIENT 81
IMAGE 3
CONTENTS VII
4.3 PRODRUG STRATEGIES TO ENHANCE LIPID SOLUBILITY 85
4.4 PRODRUG EXAMPLES FOR ANTIBIOTICS 87 4.4.1 BACAMPICILLIN 87
4.4.2 CARINDACILLIN 88
4.4.3 CEFDITOREN PIVOXIL 89 4.4.4 CEFUROXIME AXETIL 90 4.4.5 CEFPODOXIME
PROXETIL 91 4.5 ANTIVIRAL RELATED PRODRUGS 92
4.5.1 OSELTAMIVIR 92
4.5.2 FAMCICLOVIR 92
4.5.3 ADEFOVIR DIPIVOXIL 93 4.5.4 TENOFOVIR DISOPROXIL 94 4.6
CARDIOVASCULAR RELATED PRODRUGS 95 4.6.1 ENALAPRIL 95
4.6.2 FOSINOPRIL 96
4.6.3 OLMESARTAN MEDOXOMIL 97 4.7 LIPOPHILIC PRODRUGS OF BENZAMIDINE
DRUGS 98 4.7'.1 XIMELAGATRAN 98
4.7.2 DABIGATRAN ETEXILATE 99 4.8 MISCELLANEOUS EXAMPLES 100 4.8.1
CAPECITABINE 100
4.8.2 MYCOPHENOLATE MOFETIL 101 4.8.3 MISOPROSTOL 102
4.8.4 ADDITIONAL EXAMPLES 102 4.9 SUMMARY AND CONCLUSION 104
REFERENCES 106
5 MODULATING SOLUBILITY THROUGH PRODRUGS FOR ORAL AND IV DRUG DELIVERY
111 VICTOR R. GUARINO 5.1 INTRODUCTION 111
5.2 BASICS OF SOLUBILITY AND ORAL/IV DRUG DELIVERY 112 5.2.1 SOME BASIC
FUNDAMENTALS OF SOLUBILITY 112 5.2.2 SOME GENERAL COMMENTS ON IV DRUG
DELIVERY 114 5.2.3 SOME GENERAL COMMENTS ON ORAL DRUG DELIVERY 116 5.3
PRODRUG APPLICATIONS FOR ENHANCED AQUEOUS SOLUBILITY 117 5.3.1 PRODRUG
CONCEPT 117
5.3.2 EXAMPLES OF PRODRUGS TO ENHANCE AQUEOUS SOLUBILITY FOR IV
ADMINISTRATION 118 5.3.2.1 FOSPHENYTOIN 118 5.3.2.2 FOSPROPOFOL 119
5.3.2.3 PARECOXIB 120 5.3.2.4 IRINOTECAN 120 5.3.3 PRODRUGS TO ENHANCE
AQUEOUS SOLUBILITY FOR ORAL ADMINISTRATION 121
5.3.3.1 FOSAMPRENAVIR 121
IMAGE 4
VIII CONTENTS
5.3.3.2 VALGANCICLOVIR 122
5.4 CHALLENGES WITH SOLUBILIZING PRODRUGS OF INSOLUBLE DRUGS 123 5.4.1
CHALLENGES WITH SOLUBILIZING PRODRUG STRATEGIES FOR IV ADMINISTRATION
123 5.4.2 CHALLENGES WITH SOLUBILIZING PRODRUG STRATEGIES FOR
ORAL ADMINISTRATION 124 5.5 ADDITIONAL APPLICATIONS OF PRODRUGS FOR
MODULATING SOLUBILITY 125 5.5.1 ALLEVIATING PH-DEPENDENT ORAL
BIOAVAILABILITY OF WEAKLY BASIC DRUGS 126 5.5.2 ALIGNING PH-SOLUBILITY
AND PH-STABILITY RELATIONSHIPS
FOR IV PRODUCTS 126
5.5.3 MODULATING SOLUBILITY IN NEGATIVE DIRECTION 127 5.6 PARALLEL
EXPLORATION OF ANALOGUES AND PRODRUGS IN DRUG DISCOVERY (COMMENTARY) 128
5.7 CONCLUSIONS 129
REFERENCES 129
6 PRODRUGS DESIGNED TO TARGET TRANSPORTERS FOR ORAL DRUG DELIVERY 133
MARK S. WARREN AND JARKKO RAUTIO 6.1 INTRODUCTION 133
6.2 SERENDIPITY: AN ACTIVELY TRANSPORTED PRODRUG 133 6.3 REQUIREMENTS
FOR ACTIVELY TRANSPORTED PRODRUGS 135 6.4 PEPTIDE TRANSPORTERS: PEPT1
AND PEPT2 135 6.5 MONOCARBOXYLATE TRANSPORTERS 140 6.6 BILE ACID
TRANSPORTERS 143
6.7 CONCLUSIONS 147
REFERENCES 147
7 TOPICAL AND TRANSDERMAL DELIVERY USING PRODRUGS: MECHANISM OF
ENHANCEMENT 153 KENNETH SLOAN, SCOTT C. WASDO, AND SUSRUTA MAJUMDAR 7.1
INTRODUCTION 153
7.2 ARRANGEMENT OF WATER IN THE STRATUM CORNEUM 155 7.3 A NEW MODEL FOR
DIFFUSION THROUGH THE STRATUM CORNEUM: THE BIPHASIC SOLUBILITY MODEL 156
7.4 EQUATIONS FOR QUANTIFYING EFFECTS OF SOLUBILITY ON DIFFUSION
THROUGH THE STRATUM CORNEUM 158 7.4.1 THE ROBERTS-SLOAN EQUATION WHEN
THE VEHICLE IS WATER 159 7.4.2 THE ROBERTS-SLOAN EQUATION WHEN THE
VEHICLE IS A LIPID 160 7.4.3 THE SERIES/PARALLEL EQUATION WHEN THE
VEHICLE IS A LIPID 161 7.5 DESIGN OF PRODRUGS FOR TOPICAL AND
TRANSDERMAL DELIVERY
BASED ON THE BIPHASIC SOLUBILITY MODEL 162 7.5.1 5-FLUOROURACIL PRODRUGS
164 7.5.1.1 N-ACYL 5-FU PRODRUGS 165 7.5.1.2 AT-SOFT ALKYL 5-FU PRODRUGS
166
IMAGE 5
CONTENTS IX
7.5.2 ACETAMINOPHEN (APAP) PRODRUGS 167
7.5.2.1 O-ACYL APAP PRODRUGS 168 7.5.2.2 O-SOFT ALKYL APAP PRODRUGS 170
7.5.3 S-SOFT ALKYL PRODRUGS OF 6-MERCAPTOPURINE 170 7.5.3.1 EFFECT OF
VEHICLES ON TOPICAL AND TRANSDERMAL DELIVERY 171 7.6 COMPARISON OF HUMAN
AND MOUSE SKIN EXPERIMENTS 172 7.7 SUMMARY 1 74
REFERENCES 1 75
8 OCULAR DELIVERY USING PRODRUGS 181 DEEP KWATRA, RAVI VAISHYA, RIPAL
CAUDANA, JWALA JWALA, AND ASHIM K. MITRA 8.1 INTRODUCTION 181
8.2 CRITERIA FOR AN IDEAL OPHTHALMIC PRODRUG 181 8.3 ANATOMY AND
PHYSIOLOGY OF THE EYE 182 8.3.1 ANTERIOR CHAMBER 183 8.3.2 POSTERIOR
CHAMBER 183 8.4 BARRIERS TO OCULAR DRUG DELIVERY 184 8.4.1 TEAR FILM 184
8.4.2 CORNEAL EPITHELIUM 184 8.4.3 AQUEOUS HUMOR AND BAB 184 8.4.4
CONJUNCTIVA 184
8.4.5 BLOOD-RETINAL BARRIER 185 8.5 INFLUX AND EFFLUX TRANSPORTERS ON
THE EYE 185 8.6 TRANSPORTER-TARGETED PRODRUG APPROACH 186 8.6.1
ACYCLOVIR 186
8.6.2 GANCICLOVIR 188
8.6.3 QUINIDINE 188
8.7 DRUG DISPOSITION IN OCULAR DELIVERY 189 8.8 EFFECT OF PHYSIOCHEMICAL
FACTORS ON DRUG DISPOSITION IN EYE 190 8.9 PRODRUG STRATEGY TO IMPROVE
OCULAR BIOAVAILABILITY (NONTRANSPORTER-TARGETED APPROACH) 1 92
8.9.1 EPINEPHRINE 192
8.9.2 PHENYLEPHRINE 192
8.9.3 PILOCARPINE 193
8.9.4 TIMOLOL 195
8.9.5 PROSTAGLANDIN F 2A 197
8.10 RECENT PATENTS AND MARKETED OCULAR PRODRUGS 198 8.11 NOVEL
FORMULATION APPROACHES FOR SUSTAINED DELIVERY OF PRODRUGS 201 8.12
CONCLUSION 201
REFERENCES 202
9 REDUCING PRESYSTEMIC DRUG METABOLISM 207 MAJID Y. MORIDANL 9.1
INTRODUCTION 207
IMAGE 6
X CONTENTS
9.2 PRESYSTEMIC METABOLIE BARRIERS 209
9.2.1 ESTERASES 209
9.2.2 CYTOCHROME P450 ENZYMES 212 9.2.3 PHASE II DRUG METABOLIZING
ENZYMES 214 9.2.4 PEPTIDASES 215
9.2.5 OTHER OXIDATIVE METABOLIZING ENZYMES 216 9.3 PRODRUG APPROACHES TO
REDUCE PRESYSTEMIC DRUG METABOLISM 217 9.4 TARGETING COLON 220
9.5 TARGETING LYMPHATIC ROUTE 221 9.6 CONCLUSION 225
REFERENCES 226
10 ENZYME-ACTIVATED PRODRUG STRATEGIES FOR SITE-SELECTIVE DRUG DELIVERY
231 KRISTA LAINE AND KRISTIINA HUTTUNEN
10.1 INTRODUCTION 231
10.2 GENERAL REQUIREMENTS FOR ENZYME-ACTIVATED TARGETED PRODRUG STRATEGY
232 10.3 EXAMPLES OF TARGETED PRODRUG STRATEGIES 232 10.3.1 TUMOR-S
ELECTIVE PRODRUGS 232
10.3.1.1 PRODRUGS ACTIVATED BY HYPOXIA-ASSOCIATED REDUCTIVE ENZYMES 233
10.3.1.2 PRODRUGS ACTIVATED BY GLUTATHIONE S-TRANSFERASE 236 10.3.1.3
PRODRUGS ACTIVATED BY THYMIDINE PHOSPHORYLASE 237
10.3.2 ORGAN-SELECTIVE PRODRUGS 239 10.3.2.1 LIVER-TARGETED PRODRUGS 239
10.3.2.2 KIDNEY-TARGETED PRODRUGS 242 10.3.2.3 COLON-TARGETED PRODRUGS
243 10.3.3 VIRUS-SELECTIVE PRODRUGS 244 10.4 SUMMARY 245
REFERENCES 246
11 PRODRUG APPROACHES FOR CENTRAL NERVOUS SYSTEM DELIVERY 253 QUENTIN R.
SMITH AND PAUL R. LOCKMAN 11.1 BLOOD-BRAIN BARRIER IN CNS DRUG
DEVELOPMENT 253 11.2 PRODRUG STRATEGIES 255
11.3 PRODRUG STRATEGIES BASED UPON BBB NUTRIENT TRANSPORTERS 257 11.4
PRODRUG STRATEGIES BASED UPON BBB RECEPTORS 263 11.5 CNS PRODRUG SUMMARY
264 REFERENCES 266
12 DIRECTED ENZYME PRODRUG THERAPIES 271 DAN NICULESCU-DUVAZ, GABRIEL
NEGOITA-GIRAS, ION NICULESCU-DUVAZ, DOUGLAS HEDLEY, AND CAROLINE J.
SPRINGER
12.1 INTRODUCTION 271
12.2 THEORETICAL BACKGROUND OF DEPT 271
IMAGE 7
CONTENTS XI
12.2.1 ADEPT AND OTHER ENZYME-CONJUGATES APPROACHES 272
12.2.2 LIDEPT 273 12.2.3 GDEPTAND OTHER GENE DELIVERY APPROACHES 273
12.2.4 BDEPT 275
12.3 COMPARISON OF ADEPT AND GDEPT 275 12.4 ENZYMES IN ADEPT AND GDEPT
278 12.5 DESIGN OF PRODRUGS 282
12.5.1 MECHANISMS OF PRODRUG ACTIVATION 282 12.5.1.1 ELECTRONIC SWITCH
282 12.5.1.2 CELL EXCLUSION 285 12.5.1.3 BLOCKAGE OF THE PHARMACOPHORE
285 12.5.1.4 CONVERSION TO SUBSTRATE FOR ENDOGENOUS ENZYMES 287 12.5.1.5
FORMATION OF A REACTIVE MOIETY 287 12.5.1.6 FORMATION OF A SECOND
INTERACTIVE GROUP 288 12.5.2 ENZYMATIC REACTIONS ACTIVATING THE PRODRUG.
THE TRIGGER 288 12.5.2.1 REACTIONS CATALYZED BY HYDROLASES: HYDROLYTIC
CLEAVAGE 289 12.5.2.2 ACTIVATION BY NUCLEOTIDE PHOSPHORYLATION 290
12.5.2.3 ACTIVATION BY REDUCTASES 290 12.5.2.4 ACTIVATION BY OXIDASES
291 12.5.2.5 (DEOXY)RIBOSYL TRANSFER 291 12.5.3 THE LINKER.
SELF-IMMOLATIVE PRODRUGS 292 12.5.3.1 SELF-IMMOLATIVE PRODRUGS
FRAGMENTING BY ELIMINATION 293 12.5.3.2 LINKER-DRUG CONNECTION 293
12.5.3.3 SELF-IMMOLATIVE PRODRUGS FRAGMENTING FOLLOWING
CYCLIZATION 296
12.6 STRATEGIES USED FOR THE IMPROVEMENT OF DEPT SYSTEMS 296 12.6.1
IMPROVEMENT OF THE PRODRUG 296 12.6.1.1 CYTOTOXICITY DIFFERENTIAL 297
12.6.1.2 STABILITY OF PRODRUGS 298 12.6.1.3 CYTOTOXICITY AND MECHANISM
OF ACTION OF THE RELEASED DRUG 299 12.6.1.4 STABILITY OF THE RELEASED
DRUG 299 12.6.1.5 RESISTANCE (PRODRUG RELATED) 300 12.6.1.6 KINETICS OF
ACTIVATION 300 12.6.1.7 PHYSICOCHEMICAL PROPERTIES 302 12.6.1.8
PHARMACOKINETICS 303 12.6.1.9 SPECIFICITY OF ENZYME ACTIVATION 304
12.6.2 IMPROVING THE ENZYMES 304 12.6.3 THE MULTIGENE APPROACH 305
12.6.4 ENHANCING THE IMMUNE RESPONSE 307 12.7 BIOLOGICAL DATA FOR ADEPT
AND GDEPT 307 12.7.1 BACTERIA 308
12.7.2 VIRUSES 308
12.7.3 ADENOVIRAL VECTORS 308 12.7.4 POX VIRAL VECTORS 309 12.7.5
ADENO-ASSOCIATED VIRAL VECTORS 309
IMAGE 8
XII CONTENTS
12.7.6
12.7.7 12.7.8 12.7.9 12.7.10
12.7.11 12.7.12 12.7.13 12.7.14 12.8
RETROVIRAL VECTORS 309 LENTIVIRAL VECTORS 310 MEASLES VIRAL VECTORS 310
HERPES SIMPLEX VIRAL VECTORS 311 NEURAL STEM CELLS/PROGENITOR CELLS 31 J
LIPOSOMES 311 ADEPT VECTORS 312 VECTORS FOR PRODRUGS 312
CLINICAL STUDIES 316 CONCLUSIONS 316 REFERENCES 318
PART THREE CODRUGS AND SOFT DRUGS 345
13 IMPROVING THE USE OF DRUG COMBINATIONS THROUGH
THE CODRUG APPROACH 347
PETER A. CROOKS, HARPREET K. DHOOPER, AND UJJWAL CHAKRABORTY
13.1 CODRUGS AND CODRUG STRATEGY 347
13.2 IDEAL CODRUG CHARACTERISTICS 348 13.3 EXAMPLES OF MARKETED CODRUGS
349 13.4 TOPICAL CODRUG THERAPY FOR THE TREATMENT OF OPHTHALMIC DISEASES
351
13.4.1 CODRUGS FOR THE TREATMENT OF DIABETIC RETINOPATHY 351 13.4.2
CODRUGS CONTAINING CORTICOSTEROIDS FOR PROLIFERATIVE VITREORETINOPATHY
353 13.4.3 CODRUGS CONTAINING NONSTEROIDAL ANTI-INFLAMMATORY
AGENTS FOR TREATMENT OF PROLIFERATIVE VITREORETINOPATHY 355 13.4.4
CODRUGS CONTAINING ETHACRYNIC ACID FOR TREATMENT OF ELEVATED INTRAOCULAR
PRESSURE 356 13.5 CODRUGS FOR TRANSDERMAL DELIVERY 357
13.5.1 CODRUGS FOR THE TREATMENT OF ALCOHOL ABUSE AND TOBACCO DEPENDENCE
357 13.5.2 DUPLEX CODRUGS OF NALTREXONE FOR TRANSDERMAL DELIVERY 362
13.5.3 CODRUGS CONTAINING A-TOCOPHEROL FOR SKIN HYDRATION 362 13.6
CODRUGS OF L - D O PA FOR THE TREATMENT OF PARKINSON'S DISEASE 363
13.6.1 L-DOPA CODRUGS THAT INCORPORATE INHIBITORS OF L-DOPA METABOLISM
363 13.6.2 L-DOPA-ANTIOXIDANT CODRUGS 364 13.7 ANALGESIC CODRUGS
CONTAINING NONSTEROIDAL ANTI-INFLAMMATORY
AGENTS 367
13.7.1 FLURBIPROFEN-HISTAMINE H2 ANTAGONIST CODRUGS 367 13.7.2
NSAID-ACETAMINOPHEN CODRUGS 368 13.7.3 NAPROXEN-PROPYPHENAZONE CODRUGS
370 13.7.4 FLURBIPROFEN-AMINO ACID CODRUGS 371
13.7.5 NSAID-CHLORZOXAZONE CODRUGS 372
IMAGE 9
CONTENTS XIII
13.7.6 ACETAMINOPHEN-CHLORZOXAZONE CODRUG 373
13.8 ANALGESIC CODRUGS OF OPIOIDS AND CANNABINOIDS 13.9 CODRUGS
CONTAINING ANTI-HIV DRUGS 375 13.9.1 AZT-RETINOIC ACID CODRUG 377
REFERENCES 378
373
14 SOFT DRUGS 385
PAUL W. ERHARDT AND MICHAEL D. REESE 14.1 INTRODUCTION 385
14.1.1 DEFINITION 385 14.1.2 PROTOTYPICAL AGENT 386 14.1.2.1 BACKDROP
386 14.1.2.2 CLINICAL CHALLENGE 386 14.1.2.3 PHARMACOLOGICAL TARGET 388
14.1.2.4 PHARMACOLOGY, HUMAN PHARMACOKINETIC PROFILE,
AND CLINICAL DEPLOYMENT 389 14.2 INDICATIONS 390
14.2.1 A HUGE POTENTIAL 391 14.2.2 "TO MARKET, TO MARKET" 392 14.3
DESIGN CONSIDERATIONS 396 14.3.1 GENERAL REQUIREMENTS 396 14.3.2
ENZYMATIC ASPECTS 397 14.3.3 CHEMICAL STRUCTURAL ASPECTS 397 14.4 CASE
STUDY: THE DISCOVERY OF ESMOLOL 400
14.4.1 INTERNAL ESTERS 400 14.4.2 EXTERNAL ESTERS 402 14.4.3 "SQUARE
PEGS AND ROUND HOLES" 402 14.4.4 SURROGATE SCAFFOLDS FOR TESTING
PURPOSES AND A
"GLIMMER OF HOPE" 403 14.4.5 A "GOLDILOCKS" COMPOUND CALLED ESMOLOL 404
14.4.6 "ESMOLOL STAT" 406 14.4.7 CASE STUDY SUMMARY AND SOME TAKE-HOME
LESSONS
FOR TODAY 407
14.4.7.1 COMPOUND LIBRARIES 407 14.4.7.2 BIOLOGICAL TESTING 408 14.4.7.3
SAR 408 14.5 SUMMARY 408
REFERENCES 409
PART FOUR PRECLINICAL AND CLINICAL CONSIDERATION FOR PRODRUGS 415
15 PHARMACOKINETIC AND BIOPHARMACEUTICAL CONSIDERATIONS IN PRODRUG
DISCOVERY AND DEVELOPMENT 417 JOHN P. O'DONNELL 15.1 INTRODUCTION 417
IMAGE 10
XIV CONTENTS
15.2 UNDERSTANDING PHARMACOKINETIC/PHARMACODYNAMIC
RELATIONSHIPS 417
15.3 PHARMACOKINETICS 418
15.4 TOOLS FOR THE PRODRUG SCIENTIST 421 15.4.1 BIOANALYTICAL ASSAY
DEVELOPMENT 421 15.4.2 USE OF RADIOLABEL 422 15.5 ENZYMES INVOLVED WITH
PRODRUG CONVERSION 423 15.5.1 CARBOXYLESTERASES 423 15.5.2 ALKALINE
PHOSPHATASE 426 15.5.3 CYTOCHROME P450 428 15.6 USE OF THE CACO-2 SYSTEM
FOR PERMEABILITY AND ACTIVE TRANSPORT
EVALUATION 428
15.7 XP13512: IMPROVING PK PERFORMANCE BY TARGETING ACTIVE TRANSPORT 432
15.8 PRODRUG ABSORPTION: TRANSPORT/METABOLIC CONVERSION INTERPLAY 434
15.8.1 PIVAMPICILLIN 434 15.8.2 VALACYCLOVIR 436 15.9 PREABSORPTIVE
DEGRADATION 438 15.9.1 CEPHALOSPORIN PRODRUGS 438
15.9.2 SULOPENEM PRODRUGS PF-00398899, PF-03709270, AND PF-04064900 439
15.10 BIOPHARMACEUTICAL-BASED PK MODELING FOR PRODRUG DESIGN 440 15.11
CONCLUSIONS 447
REFERENCES 447
16 THE IMPACT OF PHARMACOGENETICS ON THE CLINICAL OUTCOMES OF PRODRUGS
453 JANE P.F. BAI, MIKE PACANOWSKI, ATIQUR RAHMAN, AND LAWRENCE L LESKO
16.1 INTRODUCTION 453
16.2 CLOPIDOGREL AND CYP2C19 454 16.2.1 SUMMARY 457
16.3 CODEINE AND CYP2D6 457
16.3.1 SUMMARY 460
16.4 TAMOXIFEN AND CYP2D6 460 16.4.1 SUMMARY 463
16.5 FLUOROURACIL PRODRUGS AND CARBOXYLESTERASE 464 16.5.1 CAPECITABINE
AND CARBOXYLESTERASE 465 16.5.1.1 SUMMARY 467
16.5.2 TEGAFUR AND CYP2A6 467 16.5.2.1 SUMMARY 468 16.6 IRINOTECAN AND
CARBOXYLESTERASE 2 468
16.6.1 SUMMARY 469
16.7 OTHERS 470
IMAGE 11
CONTENTS XV
16.7.1 ACE INHIBITORS AND CES 470
16.7.2 CYCLOPHOSPHAMIDE AND CYP2B6/CYP2C19 470 16.7.2.1 SUMMARY 471 16.8
DRUG DEVELOPMENT IMPLICATION 471 16.9 CONCLUSIONS 473
REFERENCES 473
INDEX 483 |
| any_adam_object | 1 |
| author2 | Rautio, Jarkko |
| author2_role | edt |
| author2_variant | j r jr |
| author_facet | Rautio, Jarkko |
| building | Verbundindex |
| bvnumber | BV036794956 |
| classification_rvk | VX 8560 |
| ctrlnum | (OCoLC)702642668 (DE-599)DNB1004024096 |
| dewey-full | 615.7 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.7 |
| dewey-search | 615.7 |
| dewey-sort | 3615.7 |
| dewey-tens | 610 - Medicine and health |
| discipline | Chemie / Pharmazie Medizin |
| format | Book |
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| indexdate | 2024-07-20T10:52:33Z |
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| isbn | 9783527326037 |
| language | English |
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| series | Methods and principles in medicinal chemistry |
| series2 | Methods and principles in medicinal chemistry |
| spelling | Prodrugs and targeted delivery towards better ADME properties ed. by Jarkko Rautio Weinheim Wiley-VCH 2011 XXIV, 496 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry 47 Targeted drug delivery (DE-588)4302415-4 gnd rswk-swf Pro-Pharmakon (DE-588)4193853-7 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Pro-Pharmakon (DE-588)4193853-7 s Targeted drug delivery (DE-588)4302415-4 s DE-604 Rautio, Jarkko edt Methods and principles in medicinal chemistry 47 (DE-604)BV035418617 47 text/html http://deposit.dnb.de/cgi-bin/dokserv?id=3498386&prov=M&dok_var=1&dok_ext=htm Inhaltstext DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=020711283&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
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| subject_GND | (DE-588)4302415-4 (DE-588)4193853-7 (DE-588)4143413-4 |
| title | Prodrugs and targeted delivery towards better ADME properties |
| title_auth | Prodrugs and targeted delivery towards better ADME properties |
| title_exact_search | Prodrugs and targeted delivery towards better ADME properties |
| title_full | Prodrugs and targeted delivery towards better ADME properties ed. by Jarkko Rautio |
| title_fullStr | Prodrugs and targeted delivery towards better ADME properties ed. by Jarkko Rautio |
| title_full_unstemmed | Prodrugs and targeted delivery towards better ADME properties ed. by Jarkko Rautio |
| title_short | Prodrugs and targeted delivery |
| title_sort | prodrugs and targeted delivery towards better adme properties |
| title_sub | towards better ADME properties |
| topic | Targeted drug delivery (DE-588)4302415-4 gnd Pro-Pharmakon (DE-588)4193853-7 gnd |
| topic_facet | Targeted drug delivery Pro-Pharmakon Aufsatzsammlung |
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