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Absorption, Gastrointestinal, 39-43 ABT-229, 244F, 245 Abzymes, 533 Index Page numbers followed by f or t indicate figures or tables, respectively. A Absorption, gastrointestinal, 39-43 ABT-229, 244f, 245 Abzymes, 533 Acetaminophen, 13f, 17 It Acetaminophen phosphate, 170t, 180 Acetanilide, 13f Acetorphan, 587 N-(N-Acetyl-L-methionyl)O,O-biscarbonyl dopamine, 346f, 347 Acetylsalicylic acid, 13f S-Acetyl thiorphan, 587 Acid-labile linkers, 509-513 Aclofenac, 663t Active effiux barrier, 578-579 Acyclovir, 22, 65, 66t, 67f, 665t aminomethylbenzoate esters, 239f prodrugs, 145, 146 see also Valacyclovir spacer groups, 391t N-Acyl derivatives, 89t, 98-101 alkylaminocarbonyl, 98-99 alkylcarbonyl, 99-101 alkyloxycarbonyl, 99 O-Acyl groups, 104t, 105-106 alkylcarbonyl derivatives, 104-106 alkyloxycarbonyl, 106 O-~N Acyl migration reaction, 189f, 190 (Acyloxyalkyl)carbamates, 137 O-Acyl peptides, 189f, 190 Adefovir, 54, 55f prodrugs see Adefovir dipivoxil Adefovir dipivoxil, 16f, 54, 55f, 160, 555f Adenosine deaminase, 609-612 ADAPT see Antibody-directed abz)~me prodrug therapy ADEPT see Antibody-directed enzyme prodrug therapy Adhesion receptors, 474-476 Adrenergic agonist prodrugs, 130-132 dipivefrin, 130, 13 If phenylephrine, 131, 132f 704 Index Ara-CMP, 556 prodrugs, YNK-01, 565f Area under concentration-time curve, 286, 432, 435-436 Asialofetuin, 558 Asialoglycoprotein receptors, 558-560 Asialoorsomucoid, 558 Aspartyl proteases, 424f AT-125, 471f Atenolol, 135 Auristatin E, 516f Avastin, 509 Axo-linked prodrugs, 687-689 6-Azauridine, 43f Azomethine prodrugs, 604-605 AZT see Zidovudine B Bacampicillin, 50, 5 If Baclofen, 587 Bambec see Bambuterol Bambuterol, 348 Benfotiamine, 63, 63f Benicar, 16f - Benzamidine prodrugs, 57 Benzoic acids, 4-substituted, 387t O-Benzoyl dextran, 386t Benzyl alcohol, 387t Benzyl elimination; 307f, 308f, 309t, 310f, 31 If amphotericin, 305, 306t, 307f daunorubicin, 303, 304t doxorubicin, 303, 305t oligonucleotides, 311, 312f, 313t, 314 proprotein conjugates, 314f, 315t, 316f vancomycin, 307f, 308f, 309t, 310f, 311f Beta-adrenergic agonist prodrugs, 135-139 nadolol, 138-139 tilisolol, 138f timolol, 135, 136t, 137f Betamethasone, 86 Betamethasone phosphate sodium, 220 Bexxar see Tositumonab Bicine/bicin prodrugs, 319f, 320f, 321,322f Bile acid transporters, 560-562 Bimatoprost, 132, 133f Bioactivation, species-dependence, 351 Index 703 Amphotericin, amine PEG prodrugs, 305, 306t, 307f Ampicillin, 49f prodrugs, 50f serum concentrations, 5 If Amprenavir, 16, 17f, 18, 162, 171t, 175 prodrugs see Fosamprenavir Analog approach, 5 Anchimeric assistance, 295 Angiogenesis, 465, 474 and hypoxia, 467 Angiotensin-converting enzyme inhibitors, 58-59, 60f Angiotension II receptor blockers, 60, 61f Aniline mustard, 461 Anionic intermediates, 600-603 phosphates, 601-603 phosphinates, 600-601 phosphonates, 601 Anthracyclines, 45 lf, 452-453 side effects, 452 see also individual drugs Antibody-directed abzyme prodrug therapy (ADAPT), 456 Antibody-directed enzyme prodrug therapy (ADEPT), 7, 11,432, 455, 479, 525-540 London group studies, 527-532 cause of myelosuppression, 530 clearing antibody, 531 fusion proteins, 531-532 pilot scale clinical trials, 529-530 prodrug and drug characteristics, 531 preclinical studies, 533-534 prodrugs, 534 Antibody-drug conjugates, 478-479 Anticancer agents see Cancer chemotherapy Antimetabolites, 451 Antiviral agents brain targeting, 595-596 prodrugs activation, 607-608 polyethylene glycol, 294 Apoptosis, 425f, 426 Aquavan see GPI 15715 1-[3-D-Arabinofuranosylcytosine prodrug, 47 lf, 472 9-[3-D-Arabinosyl-2-fluoroadenine, 227f Ara-C, 559 prodrugs MB07133, 556-558 PEG derivatives, 297, 298t, 299t 704 Index Ara-CMP, 556 prodrugs, YNK-01, 565f Area under concentration-time curve, 286, 432, 435-436 Asialofetuin, 558 Asialoglycoprotein receptors, 558-560 Asialoorsomucoid, 558 Aspartyl proteases, 424f AT-125, 471f Atenolol, 135 Auristatin E, 516f Avastin, 509 Axo-linked prodrugs, 687-689 6-Azauridine, 43f Azomethine prodrugs, 604-605 AZT see Zidovudine B Bacampicillin, 50, 5 If Baclofen, 587 Bambec see Bambuterol Bambuterol, 348 Benfotiamine, 63, 63f Benicar, 16f - Benzamidine prodrugs, 57 Benzoic acids, 4-substituted, 387t O-Benzoyl dextran, 386t Benzyl alcohol, 387t Benzyl elimination; 307f, 308f, 309t, 310f, 31 If amphotericin, 305, 306t, 307f daunorubicin, 303, 304t doxorubicin, 303, 305t oligonucleotides, 311, 312f, 313t, 314 proprotein conjugates, 314f, 315t, 316f vancomycin, 307f, 308f, 309t, 310f, 311f Beta-adrenergic agonist prodrugs, 135-139 nadolol, 138-139 tilisolol, 138f timolol, 135, 136t, 137f Betamethasone, 86 Betamethasone phosphate sodium, 220 Bexxar see Tositumonab Bicine/bicin prodrugs, 319f, 320f, 321,322f Bile acid transporters, 560-562 Bimatoprost, 132, 133f Bioactivation, species-dependence, 351 Index 705 Bioavailability, 193 Bipartate amides, 297-300 extenders, 299-300 Biphenylylacetic acid, cyclodextrin prodrugs, 69 lf, 692f, 693f Bisantrene, 230f Bispilocarpic acid mono- and diesters, 140f, 141 Blood-brain barrier, 577-579 active efflux, 578 enzymatic, 578 passive permeability, 577-578 prodrug design for CNS delivery, 579 Blood coagulation, 425f, 426 BMS-207147, 245f, 247 BMS-379224, 19f, 235f, 236 Bortezomib, 19, 20f BR96-doxorubicin, 512f, 513 BR96-phenylalanine-lysine-p-aminobenzyl-doxorubicin, 516 Brain, drug delivery, 573-651 chemical (non-enzymatic) activation, 604-606 azomethine prodrugs, 604-605 base catalyzed ring opening of temozolomide, 605-606 gene-directed enzyme prodrug therapy (GDEPT), 11,433, 455, 615, 616f lipophilic esters, 579-594 ester-activated prodrugs, 579-587 optimum lipophilicity for CNS delivery, 590-594 overcoming effiux transport, 587-590 locked-in intermediates of active drugs, 594-603 anionic intermediates, 600-603 redox trapping, 594-600 oxidoreductase-activated prodrugs, 606-608 dihydropyridine oxidation, 606 monoamine oxidase, 607 xanthine oxidase, 607-608 transferase-activated prodrugs, 609-615 adenosine deaminase, 609-612 glutathione/glutathione S-transferase, 613-615 thymidine phosphorylase/cytidine deaminase, 612-613 transporter/receptor-mediated delivery, 617-621 glucose transporter, 620, 62 If large amino acid transporter, 619, 620f receptor-mediated transcytotic pathways, 617f, 618 small molecular transporters, 618-619 Brain tissue esterase activity, 584t, 585 Bristol-Myers Squibb, 25, 236 Budenoside-[3-D-glucuronide, 690, 690f Bumetanide, 562 706 Index Buparvaquone, 171t Buparvaquone phosphate, 170t Bupranolol, 662t n-Butyric acid prodrugs, 691f Buy ins, 25 C Calcitonin prodrugs, 345t CAM 4451, 185, 187 structure, 186f Camptothecin, 292, 45 lf, 452-453 prodrugs, 248-253 glycinate ester, 249f 20-phosphoryloxymethyl derivative, 249f, 250f Camptothecin PEG derivatives, 250f, 251,293t, 294t clinical trials, 296-297 Camptothecin phosphate, 162 Canadensol, O-acyl prodrugs, 190 Cancer chemotherapy, 450, 451-453 anticancer agents, 451-453 macromolecular prodrugs, 478-479 antibody-drug conjugates, 478 polymeric drug delivery, 478 monoclonal antibody conjugates, 507-524 acid-labile linkers, 509-513 disulfide-linked conjugates, 513-515 peptide-linked conjugates, 515-518 multi-drug resistance, 450 prodrugs, 248-262, 453-454 camptothecin, 248-253 monotherapy, 454, 455f paclitaxel, 253-262 strategic considerations, 479-481 protease-activated prodrugs, 468-474 aminopeptidase-activated, 468-469 cathepsins, 470-471 matrix metalloproteinase-activated, 473-474 plasmin-activated, 471-473 prostate-specific antigens, 469 receptor binding prodrugs, 474-478 adhesion receptors, 474-476 folate receptors, 476 hormone rceptors, 476-477 releasable linkers, 456-459 targeting, 447-506 Index 707 tumor-associated targeted prodrugs, 459-474 [3-glucuronidase-activated prodrugs, 461-463 hypoxia-activated prodrugs, 459, 460f, 461 pH-sensitive prodrugs, 459 tumor-specific prodrug targets, 463-468 cathepsin B, 464 enzyme-receptor interactions, 465-468 matrix metalloproteinases, 465 plasmin and u-PA system, 464-465 two-step therapies, 455-456 see also individual agents Candesartan cilexitil, 60, 61f Cantuzumab mertansine, 513, 514f Capecitabine, 612f see also 5-Fluorouracil Capoten see Captopril Captopril, 58, 60f, 144 Carbenicillin, 69 Carbonic anhydrase inhibitor prodrugs, 142, 143f Carboxylesterases, 579-580 Carboxylic groups, 108, 109t, 110, 11 lt- 112 Carcinoembryonic antigen, 528 Carindacillin, 69 Cascade activation, 425-426 apoptosis, 425f, 426 blood coagulation, 425f, 426 Cascade-release dendrimers, 458f, 459 Catalytic triad, 422f Cathepsin-activated prodrugs, 470-471 Cathepsin B, 464, 515-516 Cathepsins, 458 CC1065, 514-515 Cefcapene pivoxil, 52 Cefditoren pivoxil, 52 Cefetamet pivoxil, 52 Cefotiam hexetil, 52 Cefpodoxime, 52 Cefteram pivoxil, 52 Ceftin see Cefuroxime axetil Cefuroxime, 52, 53f Cefuroxime axetil, 18f, 52, 53f Celecoxib, 247 CEP-5214, 186t, 187 structure, 186f Cephalexin, 144 708 Index Cephalosporins, 48f, 49, 230f, 231 absorption, 51-52 Cephazolin, 144 Cephradine, 65, 68 Cerebyx see Fosphenytoin CGH 509A, 561/ Chemical delivery systems, 594-600 Chemical (non-enzymatic) activation, 604-606 azomethine prodrugs, 604-605 base catalyzed ring opening,of temozolomide, 605-606 Chlorambucil, 662t Chloramphenicol, 14, 15t, 223, 224f 3-aminomethylbenzoate esters, 224f cycle phosphoric acid ester, 223, 224f prodrugs glycinate, 224f monosuccinate, 223, 224f palmitate, 15f 4-[(2-Chloroethyl)[2(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid, 529-530 4-Chlorokynurenine, 620f oL-Chymotrypsin, 422f Chymotrypsinogen, 420, 42 If Cidofovir, 665t Cinnarizine, 233f plasma concentrations, 234f Circulatory retention, 287-288 Clearance,
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