Prodrugs - An efficient way to breach delivery and targeting barriers

Current Topics in Medicinal Chemistry

Volumn 11, Issue 18, 2011, Pages 2265-2287

  Huttunen, Kristiina M ^a   Rautio, Jarkko ^a  

^a UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

Aqueous solubility; Drug delivery; Drug targeting; Lipophilicity; Permeability; Prodrug

Indexed keywords

2,5 BIS(4 AMIDINOPHENYL)FURAN; ACICLOVIR; ADEFOVIR DIPIVOXIL; AMINO ACID TRANSPORTER; AMINOSALICYLIC ACID; ANTINEOPLASTIC AGENT; BANOXANTRONE; BIMATOPROST; CAMPTOTHECIN; CANDESARTAN HEXETIL; CARBOHYDRATE DERIVATIVE; CYCLOPHOSPHAMIDE; DAUNORUBICIN; DEXAMETHASONE; FOSPHENYTOIN SODIUM; IFOSFAMIDE; MACROGOL DERIVATIVE; MANNICH BASE; MELAGATRAN; MEVINOLIN; ORGANOPHOSPHATE; PACLITAXEL; PAFURAMIDINE; PRADEFOVIR; PREDNISOLONE SODIUM PHOSPHATE; PRODRUG; ROLITETRACYCLINE; SIMVASTATIN; TIMOLOL; TROFOSFAMIDE; UNINDEXED DRUG; VALACICLOVIR; XIMELAGATRAN;

ALLERGY; ANEMIA; ANTIBODY DIRECTED ENZYME PRODRUG THERAPY; AQUEOUS SOLUTION; ATHEROSCLEROSIS; BACTERIAL SKIN DISEASE; BLOOD BRAIN BARRIER; BRAIN TUMOR; CYTOMEGALOVIRUS INFECTION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG PENETRATION; DRUG RELEASE; DRUG SAFETY; DRUG SOLUBILITY; DRUG TARGETING; DRUG WITHDRAWAL; EPSTEIN BARR VIRUS INFECTION; GENE DIRECTED ENZYME PRODRUG THERAPY; GLAUCOMA; GLOMERULUS FILTRATION RATE; HAIR LOSS; HEMATOLOGIC MALIGNANCY; HEPADNAVIRUS INFECTION; HERPES SIMPLEX; HERPES VIRUS INFECTION; HERPES ZOSTER; HUMAN; HYDROGEN BOND; HYPERLIPIDEMIA; HYPOXIA; INFERTILITY; LIPOPHILICITY; LIVER METABOLISM; LIVER TOXICITY; NAUSEA; NEUTROPENIA; NONHUMAN; PATIENT COMPLIANCE; PERMEABILITY BARRIER; RETROVIRUS INFECTION; REVIEW; TERATOGENICITY; THROMBOCYTOPENIA; THROMBOEMBOLISM; URINARY EXCRETION; WOUND HEALING IMPAIRMENT;

ANIMALS; DRUG DELIVERY SYSTEMS; HUMANS; PERMEABILITY; PRODRUGS; SOLUBILITY;

EID: 80052194307     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/156802611797183230     Document Type: Review

References (194)

1. Kerns, E.H.; Di, L. Pharmaceutical profiling in drug discovery. Drug Discov. Today,2003, 8, 316-323.
2. Stella, V.J.; Borchardt, R.T.; Hageman, M.J.; Oliyai, R.; Maag, H.; Tilley, J.W. Prodrugs: Challenges and Rewards Part 1 & 2; Springer Science + Business Media: New York, 2007.
3. Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov., 2008, 7, 255-270.
4. Ettmayer, P.; Amidon, G.L.; Clement, B.; Testa, B. Lessons learned from marketed and investigational prodrugs. J. Med. Chem., 2004, 47, 2393-2404.
5. Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421-422.
6. Stella, V.J. Prodrugs as therapeutics. Expert Opin. Ther. Pat. 2004, 14, 277-280.
7. Testa, B. Prodrug research: futile or fertile? Biochem. Pharmacol., 2004, 68, 2097-2106.
8. Papot, S.; Tranoy, I.; Tillequin, F.; Florent, J.C.; Gesson, J.P. Design of selectively activated anticancer prodrugs: elimination and cyclization strategies. Curr. Med. Chem. Anticancer Agents, 2002, 2, 155-185.
9. Boucher, B.A. Fosphenytoin: A Novel phenytoin prodrug. Pharmacotherapy, 1996, 16, 777-791.
10. Florent, J.C.; Dong, X.; Gaudel, G.; Mitaku, S.; Monneret, C.; Gesson, J.P.; Jacquesy, J.C.; ondon, M.; Renoux, B.; Andrianomenjanahary, S.; Michel, S.; Koch, M.; Tillequin, F.; Gerken, M.; Czech, J.; Straub, R.; Bosslet, K. Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy. J. Med. Chem., 1998, 41, 3572-3581.
11. Huttunen, K.M.; Kumpulainen, H.; Leppänen, J.; Rautio, J.; Järvinen, T.; Vepsäläinen, J. Efficient strategy to prepare water-soluble prodrugs of ketones. Synlett, 2006, 5, 701-704.
12. Clement, B.; Lopian, K. Characterization of in Vitro Biotransfor-mation of new, orally active, direct thrombin inhibitor ximelaga-tran, an amidoxime and ester Prodrug. Drug Metab. Dispos., 2003, 31, 645-651.
13. Testa, B.; Mayer, J.M., Concepts in Prodrug Design to Overcome Pharmacokinetic Problems. In Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Strategies; Testa, B.; van De Waterbeemd, H.; Folkers, G.; Guy, R.; Eds; Verlag Helvetica Chimica Acta and Wiley-VCH: Zürich and Weinheim, 2001.
14. Stella, V.J.; Nti-Addae, K.W. Prodrug strategies to overcome poor water solubility. Adv. Drug Deliv. Rev., 2007, 59, 677-694.
15. Fleisher, D.; Bong, R.; Stewart, B.H. Improved oral drug delivery: solubility limitations overcome by the use of prodrugs. Adv. Drug Deliv. Rev., 1996, 19, 115.
16. Schmidt, F.; Monneret, C. Prodrug Mono Therapy: synthesis and biological evaluation of an etoposide glucuronide-prodrug. Bioorg. Med. Chem., 2003, 11, 2277-2283.
17. Krise, J.P.; Stella, V.J. Prodrugs of phosphates, phosphonates, and phosphinates. Adv. Drug Deliv. Rev., 1996, 19, 287.
18. McComb, R.B.; Bower Jr, G.N.; Posen, S. Alkaline Phosphatase; Plenum Press: New York, 1979.
19. Krise, J.P.; Zygmunt, J.; Georg, G.I.; Stella, V.J. Novel prodrug approach for tertiary amines: synthesis and preliminary evaluation of n-phosphonooxymethyl prodrugs. J. Med. Chem., 1999, 42, 3094-3100.
20. Safadi, M.; Oliyai, R.; Stella, V.J. Phosphoryloxymethyl carba-mates and carbonates--novel water-soluble prodrugs for amines and hindered alcohols. Pharm. Res., 1993, 10, 1350-1355.
21. Sousa, F.J. The bioavailability and therapeutic effectiveness of prednisolone acetate Vs. prednisolone sodium phosphate: A 20-year review. Clao. J., 1991, 17, 282-284.
22. Dhareshwar, S.S.; Stella, V.J. Your prodrug releases formaldehyde: Should you be concerned? no! J. Pharm. Sci., 2008, 97, 4184-4193.
23. Kwon, Y. Handbook of Essential Pharmacokinetics, Pharmacody-namics and Drug Metabolism for Industrial Scientists; Kluwer Academic Publishers: Hingham, 2002.
24. Chan, O.H.; Schmid, H.L.; Stilgenbauer, L.A.; Howson, W.; Hor-well, D.C.; Stewart, B.H. Evaluation of a targeted prodrug strategy of enhance oral absorption of poorly water-soluble compounds. Pharm. Res., 1998, 15, 1012-1018.
25. Pochopin, N.L.; Charman, W.N.; Stella, V.J. Pharmacokinetics of dapsone and amino acid prodrugs of dapsone. Drug. Metab. Dis-pos., 1994, 22, 770-775.
26. Pochopin, N.L.; Charman, W.N.; Stella, V.J. Amino acid derivatives of dapsone as water-soluble prodrugs. Int. J. Pharm., 1995, 121, 157-167.
27. Bröer, S. Amino Acid Transport across Mammalian Intestinal and Renal Epithelia. Physiol. Rev., 2008, 88, 249-286.
28. Amidon, G.L.; Sadée, W. Memrane Transporters as Drug Tar-gets;Borchardt, R.T.;Ed; Kluwer Academic Publishers: New York, 2002.
29. Majumdar, S.; Duvvuri, S.; Mitra, A.K. Membrane transporter/receptor-targeted prodrug design: strategies for human and veterinary drug development. Adv. Drug Deliv. Rev., 2004, 56, 1437-1452.
30. Granero, G.E.; Amidon, G.L. Stability of valacyclovir: implications for its oral bioavailability. Int. J. Pharm., 2006, 317, 14-18.
31. Anand, B.S.; Katragadda, S.; Mitra, A.K. Pharmacokinetics of novel dipeptide ester prodrugs of acyclovir after oral administration: intestinal absorption and liver metabolism. J. Pharmacol. Exp. Ther., 2004, 311, 659-667.
32. 0,+ as a delivery system for drugs and Prodrugs. Curr. Drug Targets Immune Endocr. Metabol. Disord., 2005, 5, 357-364.
33. Burnette, T.C.; Harrington, J.A.; Reardon, J.E.; Merrill, B.M.; de Miranda, P. Purification and characterization of a rat liver enzyme that hydrolyzes valaciclovir, the l-valyl ester prodrug of acyclovir. J. Biol. Chem., 1995, 270, 15827-15831.
34. Leenders, R.G.; Damen, E.W.; Bijsterveld, E.J.; Scheeren, H.W.; Houba, P.H.; van der Meulen-Muileman, I.H.; Boven, E.; Haisma, H.J. Novel anthracycline-spacer-ß-glucuronide,-ß-glucoside, and -ß-galactoside Prodrugs for application in selective chemotherapy. Bioorg. Med. Chem., 1999, 7, 1597-1610.
35. Mikuni, K.; Nakanishi, K.; Hara, K.; Hara, K.; Iwatani, W.; Amano, T.; Nakamura, K.; Tsuchiya, Y.; Okumoto, H.; Mandai, T. In vivo antitumor activity of novel water-soluble taxoids. Biol. Pharm. Bull., 2008, 31, 1155-1158.
36. de Graaf, M.; Pinedo, H.M.; Quadir, R.; Haisma, H.J.; Boven, E. Cytosolic ß-glycosidases for activation of glycoside prodrugs of daunorubicin. Biochem. Pharmacol., 2003, 65, 1875-1881.
37. de Bont, D.B.; Leenders, R.G.; Haisma, H.J.; van der Meulen-Muileman, I.; Scheeren, H.W. Synthesis and biological activity of ß-glucuronyl carbamate-based prodrugs of paclitaxel as potential candidates for adept. Bioorg. Med. Chem., 1997, 5, 405-414.
38. Mürdter, T.E.; Sperker, B.; Kivisto, K.T.; McClellan, M.; Fritz, P.; Friedel, G.; Linder, A.; Bosslet, K.; Toomes, H.; Dierkesmann, R.; Kroemer, H.K. Enhanced uptake of doxorubicin into bronchial carcinoma: ß-Glucuronidase mediates release of doxorubicin from a glucuronide prodrug (Hmr 1826) at the tumor site. Cancer Res., 1997, 57, 2440-2445.
39. Greenwald, R.B.; Gilbert, C.W.; Pendri, A.; Conover, C.D.; Xia, J.; Martinez, A. Drug delivery systems: water soluble taxol 2'-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness. J. Med. Chem., 1996, 39, 424-431.
40. Li, C.; Yu, D.; Inoue, T.; Yang, D.J.; Milas, L.; Hunter, N.R.; Kim, E.E.; Wallace, S. Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug. Anti-Cancer Drugs, 1996, 7, 642-648.
41. Pendri, A.; Conover, C.D.; Greenwald, R.B. Antitumor activity of paclitaxel-2'-glycinate conjugated to poly(ethylene glycol): A water-soluble prodrug. Anticancer Drug Des., 1998, 13, 387-395.
42. Feng, X.; Yuan, Y.J.; Wu, J.C. Synthesis and evaluation of water-soluble paclitaxel prodrugs. Bioorg. Med. Chem. Lett., 2002, 12, 3301-3303.
43. Ryu, B.Y.; Sohn, J.S.; Hess, M.; Choi, S.K.; Choi, J.K.; Jo, B.W. Synthesis and anti-cancer efficacy of rapid hydrolysed water-soluble paclitaxel pro-drugs. J. Biomater. Sci. Polym. Ed., 2008, 19, 311-324.
44. Greenwald, R.B.; Zhao, H.; Xia, J. Tripartate poly(ethylene glycol) prodrugs of the open lactone form of camptothecin. Bioorg. Med. Chem., 2003, 11, 2635-2639.
45. Zhao, H.; Rubio, B.; Sapra, P.; Wu, D.; Reddy, P.; Sai, P.; Martinez, A.; Gao, Y.; Lozanguiez, Y.; Longley, C.; Greenberger, L.M.; Horak, I.D. Novel prodrugs of Sn38 using multiarm poly(ethylene glycol) linkers. Bioconjug. Chem., 2008, 19, 849-859.
46. Greenwald, R.B.; Pendri, A.; Conover, C.D.; Zhao, H.; Choe, Y.H.; Martinez, A.; Shum, K.; Guan, S. Drug delivery systems employing 1,4- or 1,6-elimination: poly(ethylene glycol) prodrugs of amine-containing compounds. J. Med. Chem., 1999, 42, 3657-3667.
47. Harris, J.M.; Chess, R.B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov., 2003, 2, 214-221.
48. Taylor, M.D. Improved passive oral drug delivery via prodrugs. Adv. Drug Deliv. Rev., 1996, 19, 131-148.
49. Liederer, B.M.; Borchardt, R.T. Enzymes involved in the biocon-version of ester-based prodrugs. J. Pharm. Sci., 2006, 95, 1177-1195.
50. Hu, L., Prodrug Approaches to Drug Delivery. In Drug Delivery: Principles and Applications Wang, B.; Ed; John Wiley & Sons, Inc., Hoboken, 2005.
51. Chang, S.C.; Bundgaard, H.; Buur, A.; Lee, V.H. Improved corneal penetration of timolol by prodrugs as a means to reduce systemic drug load. Invest. Ophthalmol. Vis. Sci., 1987, 28, 487-491.
52. Chien, D.S.; Sasaki, H.; Bundgaard, H.; Buur, A.; Lee, V.H. Role of enzymatic lability in the corneal and conjunctival penetration of timolol ester prodrugs in the pigmented rabbit. Pharm. Res., 1991, 8, 728-733.
53. Benzaria, S.; Pelicano, H.; Johnson, R.; Maury, G.; Imbach, J.L.; Aubertin, A.M.; Obert, G.; Gosselin, G. Synthesis, in vitro antiviral evaluation, and stability studies of Bis-(S-Acyl-2-Thioethyl) ester derivatives of 9-[2-(Phosphonomethoxy)Ethyl]adenine (Pmea) as potential pmea prodrugs with improved oral bioavailability. J. Med. Chem., 1996, 39, 4958-4965.
54. Noble, S.; Goa, K.L. Adefovir dipivoxil. Drugs, 1999, 58, 479-487.
55. Qandil, A.; Al-Nabulsi, S.; Al-Taani, B.; Tashtoush, B. Synthesis of piperazinylalkyl ester prodrugs of ketorolac and their in vitro evaluation for transdermal delivery. Drug Dev. Ind. Pharm., 2008, 34(10), 1054-1063.
56. Hecker, S.J.; Erion, M.D. Prodrugs of phosphates and phospho-nates. J. Med. Chem., 2008, 51, 2328-2345.
57. Gustafsson, D.; Nystrom, J.; Carlsson, S.; Bredberg, U.; Eriksson, U.; Gyzander, E.; Elg, M.; Antonsson, T.; Hoffmann, K.; Ungell, A.; Sorensen, H.; Nagard, S.; Abrahamsson, A.; Bylund, R. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: Intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb. Res., 2001, 101, 171-181.
58. Zhou, L.; Lee, K.; Thakker, D.R.; Boykin, D.W.; Tidwell, R.R.; Hall, J.E. Enhanced permeability of the antimicrobial agent 2,5-Bis-(4-Amidinophenyl)furan across Caco-2 cell monolayers via its methylamidoidme prodrug. Pharm. Res., 2002, 19, 1689-1695.
59. Sharif, N.A.; Kelly, C.R.; Crider, J.Y.; Williams, G.W.; Xu, S.X. Ocular hypotensive Fp prostaglandin (Pg) analogs: Pg receptor subtype binding affinities and selectivities, and agonist potencies at fp and other pg receptors in cultured cells. J. Ocul. Pharmacol. Ther., 2003, 19, 501-515.
60. Caro, A.A.; Cederbaum, A.I.; Stoyanovsky, D.A. Oxidation of the ketoxime acetoxime to nitric oxide by oxygen radical-generating systems. Nitric. Oxide, 2001, 5, 413-424.
61. Clement, B. Reduction of N-hydroxylated compounds: amidoximes (N-Hydroxyamidines) as pro-drugs of amidines. Drug Metab. Rev., 2002, 34, 565-579.
62. Huttunen, K.M.; Mähönen, N.; Raunio, H.; Rautio, J. Cytochrome P450-activated prodrugs: targeted drug delivery. Curr. Med. Chem., 2008, 15, 2346-2365.
63. Guengerich, F.P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol., 2001, 14, 611-650.
64. Pelkonen, O.; Turpeinen, M.; Hakkola, J.; Honkakoski, P.; Huk-kanen, J.; Raunio, H. Inhibition and Induction Of Human cyto-chrome P450 Enzymes: Current Status. Arch. Toxicol., 2008, 82, 667-715.
65. Clement, B.; Lomb, R.; Moller, W. Isolation and characterization of the protein components of the liver microsomal O2-insensitive nadh-benzamidoxime reductase. J. Biol. Chem., 1997, 272, 19615-19620.
66. Kurian, J.R.; Bajad, S.U.; Miller, J.L.; Chin, N.A.; Trepanier, L.A. Nadh cytochrome B5 reductase and cytochrome B5 catalyze the mi-crosomal reduction of xenobiotic hydroxylamines and amidoximes in humans. J. Pharmacol. Exp. Ther., 2004, 311, 1171-1178.
67. Mäntylä, A.; Rautio, J.; Nevalainen, T.; Keski-Rahkonen, P.; Vep-säläinen, J.; Järvinen, T. Design, synthesis and in vitro evaluation of novel water-soluble prodrugs of Buparvaquone. Eur. J. Pharm. Sci., 2004, 23, 151-158.
68. Zhou, L.; Thakker, D.R.; Voyksner, R.D.; Anbazhagan, M.; Boykin, D.W.; Hall, J.E.; Tidwell, R.R. Metabolites of an orally active antimicrobial prodrug, 2,5-Bis-(4-Amidinophenyl)furan-bis-O-methylamidoxime, identified by liquid chromatography/tandem mass spectrometry. J. Mass. Spectrom., 2004, 39, 351-360.
69. Saulter, J.Y.; Kurian, J.R.; Trepanier, L.A.; Tidwell, R.R.; Bridges, A.S.; Boykin, D.W.; Stephens, C.E.; Anbazhagan, M.; Hall, J.E. Unusual dehydroxylation of antimicrobial amidoxime prodrugs by cytochrome b5 and nadh cytochrome B5 reductase. Drug Metab. Dispos., 2005, 33, 1886-1893.
70. Wang, M.Z.; Saulter, J.Y.; Usuki, E.; Cheung, Y.L.; Hall, M.; Bridges, A.S.; Loewen, G.; Parkinson, O.T.; Stephens, C.E.; Allen, J.L.; Zeldin, D.C.; Boykin, D.W.; Tidwell, R.R.; Parkinson, A.; Paine, M.F.; Hall, J.E. Cyp4f enzymes are the major enzymes in human liver microsomes that catalyze the o-demethylation of the antiparasitic prodrug Db289 [2,5-Bis-(4-Amidinophenyl)Furan-Bis-O-Methylamidoxime]. Drug Metab. Dispos., 2006, 34, 1985-1994.
71. Wang, M.Z.; Wu, J.Q.; Bridges, A.S.; Zeldin, D.C.; Kornbluth, S.; Tidwell, R.R.; Hall, J.E.; Paine, M.F. Human enteric microsomal Cyp4f enzymes O-demethylate the antiparasitic prodrug pafura-midine. Drug Metab. Dispos., 2007, 35, 2067-2075.
72. Midgley, I.; Fitzpatrick, K.; Taylor, L.M.; Houchen, T.L.; Henderson, S.J.; Wright, S.J.; Cybulski, Z.R.; John, B.A.; McBur-ney, A.; Boykin, D.W.; Trendler, K.L. Pharmacokinetics and metabolism of the prodrug Db289 (2,5-Bis-[4-(N-Methoxyamidino)Phenyl]Furan Monomaleate) in rat and monkey and its conversion to the antiprotozoal/antifungal drug Db75 (2,5-Bis-(4-Guanylphenyl)furan Dihydrochloride). Drug Metab. Dis-pos., 2007, 35, 955-967.
73. U. S. National Institutes of Health, Nct00408369. [cited 2.7.2009]; Available from: http://www.clinicaltrials.gov/ct2/show/NCT00408369?term=pafura midine&rank=2.
74. Gustafsson, D.; Elg, M. The Pharmacodynamics and pharmacoki-netics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: A mini-review. Thromb. Res., 2003, 109 (Suppl 1), S9-15.
75. Eriksson, U.G.; Bredberg, U.; Hoffmann, K.J.; Thuresson, A.; Gabrielsson, M.; Ericsson, H.; Ahnoff, M.; Gislen, K.; Fager, G.; Gustafsson, D. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab. Dispos., 2003, 31, 294-305.
76. Astrazeneca Clinical Trials - Exanta (Ximelagatran) Clinical Trial Summary. [cited 2.7.2009]; Available from: http://www.astrazenecaclinicaltrials.com/clinicaltrials/exanta/.
77. Simplicio, A.L.; Clancy, J.M.; Gilmer, J.F. ß-Aminoketones as prodrugs with Ph-controlled activation. Int. J. Pharm., 2007, 336, 208-214.
78. Petrak, K. Essential properties of drug-targeting delivery systems. Drug Discov. Today, 2005, 10, 1667-1673.
79. Wagner, V.; Dullaart, A.; Bock, A.K.; Zweck, A. The emerging nanomedicine landscape. Nat. Biotechnol., 2006, 24, 1211-1217.
80. Caruthers, S.D.; Wickline, S.A.; Lanza, G.M. Nanotechnological applications in medicine. Curr. Opin. Biotechnol., 2007, 18, 26-30.
81. Denny, W.A. Prodrug strategies in cancer therapy. Eur. J. Med. Chem., 2001, 36, 577-595.
82. Shanghag, A.; Yam, N.; Jasti, B. Prodrugs as Drug Delivery Systems. In: Design of Controlled Release Drug Delivery Systems; Li, X.; Jasti, B.R.; Eds; The McGraw-Hill Company, Inc.: New York, 2006.
83. Järvinen, T.; Rautio, J.; Masson, M.; Loftsson, T., Design and Pharmaceutical Applications of Prodrugs. In Drug Discovery Handbook Gad, S.C.; Ed; John Wiley & Sons, Inc.: New Jersey, 2005.
84. Bishop, J.F. Cancer Fact: A Concise Oncology Text; Overseas Publishers Association: Amsterdam, 1999.
85. Rooseboom, M.; Commandeur, J.N.; Vermeulen, N.P. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol. Rev., 2004, 56, 53-102.
86. Zhang, J.; Tian, Q.; Yung Chan, S.; Chuen Li, S.; Zhou, S.; Duan, W.; Zhu, Y.Z. Metabolism and transport of oxazaphosphorines and the clinical implications. Drug Metab. Rev., 2005, 37, 611-703.
87. Kan, O.; Griffiths, L.; Baban, D.; Iqball, S.; Uden, M.; Spearman, H.; Slingsby, J.; Price, T.; Esapa, M.; Kingsman, S.; Kingsman, A.; Slade, A.; Naylor, S. Direct Retroviral delivery of human cyto-chrome P450 2b6 for gene-directed enzyme prodrug therapy of cancer. Cancer Gene Ther., 2001, 8, 473-482.
88. Braybrooke, J.P.; Slade, A.; Deplanque, G.; Harrop, R.; Madhusu-dan, S.; Forster, M.D.; Gibson, R.; Makris, A.; Talbot, D.C.; Steiner, J.; White, L.; Kan, O.; Naylor, S.; Carroll, M.W.; Kingsman, S.M.; Harris, A.L. Phase I study of metxia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma. Clin. Cancer Res., 2005, 11, 1512-1520.
89. Bosslet, K.; Straub, R.; Blumrich, M.; Czech, J.; Gerken, M.; Sperker, B.; Kroemer, H.K.; Gesson, J.P.; Koch, M.; Monneret, C. Elucidation of the mechanism enabling tumor selective prodrug monotherapy. Cancer Res., 1998, 58, 1195-1201.
90. Mürdter, T.E.; Friedel, G.; Backman, J.T.; McClellan, M.; Schick, M.; Gerken, M.; Bosslet, K.; Fritz, P.; Toomes, H.; Kroemer, H.K.; Sperker, B. Dose optimization of a doxorubicin prodrug (Hmr 1826) in isolated perfused human lungs: Low tumor Ph promotes prodrug activation by ß-glucuronidase. J. Pharmacol. Exp. Ther., 2002, 301, 223-228.
91. Platel, D.; Bonoron-Adele, S.; Dix, R.K.; Robert, J. Preclinical evaluation of the cardiac toxicity of Hmr-1826, a novel prodrug of doxorubicin. Br. J. Cancer, 1999, 81, 24-27.
92. Huang, P.S.; Oliff, A. Drug-targeting strategies in cancer therapy. Curr. Opin. Genet. Dev. 2001, 11, 104-110.
93. Heine, D.; Muller, R.; Brusselbach, S. Cell surface display of a lysosomal enzyme for extracellular gene-directed enzyme prodrug therapy. Gene Ther., 2001, 8, 1005-1010.
94. Sperker, B.; Murdter, T.E.; Backman, J.T.; Fritz, P.; Kroemer, H.K. Expression of active human ß-glucuronidase in Sf9 cells infected with recombinant baculovirus. Life Sci., 2002, 71, 1547-1557.
95. Miller, S.D.; Mohiuddin, I.; Cao, X.X.; Ozvaran, M.K.; Daniel, J.C.; Roy Smythe, W. Gene therapy for sarcoma utilizing adenoviral transfer of the ß-glucuronidase and bax genes and an anthra-cyline prodrug. J. Surg. Res., 2004, 121, 153-158.
96. Teicher, B.A.; Kowal, C.D.; Kennedy, K.A.; Sartorelli, A.C. Enhancement by hyperthermia of the in vitro cytotoxicity of mitomy-cin C toward hypoxic tumor cells. Cancer Res. 1981, 41, 1096-1099.
97. 1. Cancer Res., 1992, 52, 4752-4757.
98. Li, D.; Gan, Y.; Wientjes, M.G.; Badalament, R.A.; Au, J.L. Distribution of Dt-diaphorase and reduced nicotinamide adenine dinucleotide phosphate: Cytochrome P450 oxidoreductase in bladder tissues and tumors. J. Urol., 2001, 166, 2500-2505.
99. Spanswick, V.J.; Cummings, J.; Smyth, J.F. Current issues in the enzymology of mitomycin C metabolic activation. Gen. Pharmacol., 1998, 31, 539-544.
100. Rauth, A.M.; Melo, T.; Misra, V. Bioreductive therapies: an overview of drugs and their mechanisms of action. Int. J. Radiat. Oncol. Biol. Phys., 1998, 42, 755-762.
101. McKeown, S.R.; Cowen, R.L.; Williams, K.J. Bioreductive drugs: from concept to clinic. Clin. Oncol., (R. Coll. Radiol.) 2007, 19, 427-442.
102. Guise, C.P.; Wang, A.T.; Theil, A.; Bridewell, D.J.; Wilson, W.R.; Patterson, A.V. Identification of human reductases that activate the dinitrobenzamide mustard prodrug Pr-104a: A role for nadph:cytochrome P450 oxidoreductase under Hypoxia. Biochem. Pharmacol., 2007, 74, 810-820.
103. Patterson, L.H. Bioreductively activated antitumor N-Oxides: The case of aq4n, a unique approach to hypoxia-activated cancer chemotherapy. Drug Metab. Rev., 2002, 34, 581-592.
104. Raleigh, S.M.; Wanogho, E.; Burke, M.D.; McKeown, S.R.; Patterson, L.H. Involvement of human cytochromes P450 (Cyp) in the reductive metabolism of Aq4n, a hypoxia activated anthraquinone Di-N-Oxide prodrug. Int. J. Radiat. Oncol. Biol. Phys., 1998, 42, 763-767.
105. Albertella, M.R.; Loadman, P.M.; Jones, P.H.; Phillips, R.M.; Rampling, R.; Burnet, N.; Alcock, C.; Anthoney, A.; Vjaters, E.; Dunk, C.R.; Harris, P.A.; Wong, A.; Lalani, A.S.; Twelves, C.J. Hypoxia-selective targeting by the bioreductive prodrug Aq4n in patients with solid tumors: results of a phase I study. Clin. Cancer Res., 2008, 14, 1096-1104.
106. McCarthy, H.O.; Yakkundi, A.; McErlane, V.; Hughes, C.M.; Keilty, G.; Murray, M.; Patterson, L.H.; Hirst, D.G.; McKeown, S.R.; Robson, T. Bioreductive gdept using cytochrome P450 3a4 in combination with Aq4n. Cancer Gene Ther., 2003, 10, 40-48.
107. McErlane, V.; Yakkundi, A.; McCarthy, H.O.; Hughes, C.M.; Patterson, L.H.; Hirst, D.G.; Robson, T.; McKeown, S.R. A Cytochrome P450 2b6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug Aq4n. J. Gene Med., 2005, 7, 851-859.
108. Yakkundi, A.; McErlane, V.; Murray, M.; McCarthy, H.O.; Ward, C.; Hughes, C.M.; Patterson, L.H.; Hirst, D.G.; McKeown, S.R.; Robson, T. Tumor-selective drug activation: a gdept approach utilizing cytochrome P450 1a1 and Aq4n. Cancer Gene Ther., 2006, 13, 598-605.
109. Fitzsimmons, S.A.; Lewis, A.D.; Riley, R.J.; Workman, P. Reduction of 3-Amino-1,2,4-Benzotriazine-1,4-Di-N-Oxide (Tira-pazamine, Win 59075, Sr 4233) to a DNA-Damaging Species: A Direct Role for Nadph:Cytochrome P450 Oxidoreductase. Car-cinogenesis, 1994, 15, 1503-1510.
110. Patterson, A.V.; Barham, H.M.; Chinje, E.C.; Adams, G.E.; Harris, A.L.; Stratford, I.J. Importance of P450 reductase activity in determining sensitivity of breast tumour cells to the bioreductive drug, tirapazamine (Sr 4233). Br. J. Cancer, 1995, 72, 1144-1150.
111. Zeman, E.M.; Brown, J.M.; Lemmon, M.J.; Hirst, V.K.; Lee, W.W. Sr-4233: A new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int. J. Radiat. Oncol. Biol. Phys., 1986, 12, 1239-1242.
112. Baker, M.A.; Zeman, E.M.; Hirst, V.K.; Brown, J.M. Metabolism of Sr 4233 by chinese hamster ovary cells: basis of selective hy-poxic cytotoxicity. Cancer Res., 1988, 48, 5947-5952.
113. von Pawel, J.; von Roemeling, R.; Gatzemeier, U.; Boyer, M.; Elisson, L.O.; Clark, P.; Talbot, D.; Rey, A.; Butler, T.W.; Hirsh, V.; Olver, I.; Bergman, B.; Ayoub, J.; Richardson, G.; Dunlop, D.; Arcenas, A.; Vescio, R.; Viallet, J.; Treat, J. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: A report of the international catapult i study group. cisplatin and tira-pazamine in subjects with advanced previously untreated non-small-cell lung tumors. J. Clin. Oncol., 2000, 18, 1351-1359.
114. Cowen, R.L.; Williams, K.J.; Chinje, E.C.; Jaffar, M.; Sheppard, F.C.; Telfer, B.A.; Wind, N.S.; Stratford, I.J. Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting Cure. Cancer Res., 2004, 64, 1396-1402.
115. Patterson, A.V.; Ferry, D.M.; Edmunds, S.J.; Gu, Y.; Singleton, R.S.; Patel, K.; Pullen, S.M.; Hicks, K.O.; Syddall, S.P.; Atwell, G.J.; Yang, S.; Denny, W.A.; Wilson, W.R. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent Pr-104. Clin. Cancer Res., 2007, 13, 3922-3932.
116. Zonderman, J.; Vender, R. Understanding Crohn Disease and Ul-cerative Colitis.; University Press of Mississippi: Jackson, 2000.
117. Adrouny, A.R. Understanding Colon Cancer.; University Press of Mississippi: Jackson, 2002.
118. Chourasia, M.K.; Jain, S.K. Pharmaceutical approaches to colon targeted drug delivery systems. J. Pharm. Pharm. Sci., 2003, 6, 33-66.
119. Friend, D.R. New oral delivery systems for treatment of inflammatory bowel disease. Adv. Drug Deliv. Rev., 2005, 57, 247-265.
120. Scheline, R.R. Metabolism of foreign compounds by gastrointestinal microorganisms. Pharmacol. Rev., 1973, 25, 451-523.
121. van Hees, P.A.; van Lier, H.J.; van Elteren, P.H.; Driessen, M.; van Hogezand, R.A.; Ten Velde, G.P.; Bakker, J.H.; van Tongeren, J.H. Effect of sulphasalazine in patients with active crohn's disease: A controlled double-blind study. Gut, 1981, 22, 404-409.
122. Azadkhan, A.K.; Truelove, S.C.; Aronson, J.K. The disposition and metabolism of sulphasalazine (Salicylazosulphapyridine) in man. Br. J. Clin. Pharmacol., 1982, 13, 523-528.
123. Willoughby, C.P.; Aronson, J.K.; Agback, H.; Bodin, N.O.; True-love, S.C. Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis. Gut, 1982, 23, 1081-1087.
124. van Hogezand, R.A.; van Hees, P.A.; Zwanenburg, B.; van Rossum, J.M.; van Tongeren, J.H. Disposition of disodium azodisalicy-late in healthy subjects. A Possible new drug for inflammatory bowel disease. Gastroenterology, 1985, 88, 717-722.
125. McIntyre, P.B.; Rodrigues, C.A.; Lennard-Jones, J.E.; Barrison, I.G.; Walker, J.G.; Baron, J.H.; Thornton, P.C. Balsalazide in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine. Aliment. Pharmacol. Ther., 1988, 2, 237-243.
126. Friend, D.R.; Chang, G.W. A Colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria. J. Med. Chem., 1984, 27, 261-266.
127. Haeberlin, B.; Rubas, W.; Nolen, H.W., 3rd; Friend, D.R. In vitro evaluation of dexamethasone-ß-d-glucuronide for colon-specific drug delivery. Pharm. Res., 1993, 10, 1553-1562.
128. Ruiz, J.F.; Radics, G.; Windle, H.; Serra, H.O.; Simplicio, A.L.; Kedziora, K.; Fallon, P.G.; Kelleher, D.P.; Gilmer, J.F. Design, synthesis, and pharmacological effects of a cyclization-activated steroid prodrug for colon targeting in inflammatory bowel disease. J. Med. Chem., 2009, 52, 3205-3211.
129. Jung, Y.J.; Lee, J.S.; Kim, Y.M. Colon-specific prodrugs of 5-aminosalicylic acid: synthesis and in vitro/in vivo properties of acidic amino acid derivatives of 5-aminosalicylic acid. J. Pharm. Sci., 2001, 90, 1767-1775.
130. El-Kamel, A.H.; Abdel-Aziz, A.A.; Fatani, A.J.; El-Subbagh, H.I. Oral colon targeted delivery systems for treatment of inflammatory bowel diseases: synthesis, in vitro and in vivo assessment. Int. J. Pharm., 2008, 358, 248-255.
131. th Ed.; Vol. 1; Elsevier, Inc.: Philadelphia, 2006.
132. Worman, H.J. The Liver Disorders and Hepatic Sourcebook; McGraw-Hill, Inc: New York, 2006.
133. Smith, D.A.; Ackland, M.J.; Jones, B.C. Properties of cytochrome P450 isoenzymes and their substrates. part 1: active site characteristics. Drug Discov. Today, 1997, 2, 406-414.
134. Lewis, D.F.; Dickins, M. Substrate sars in human P450s. Drug Discov. Today, 2002, 7, 918-925.
135. Nebert, D.W.; Russell, D.W. Clinical importance of the cyto-chromes P450. Lancet, 2002, 360, 1155-1162.
136. Bruno, R.D.; Njar, V.C. Targeting cytochrome P450 enzymes: A new approach in anti-cancer drug development. Bioorg. Med. Chem., 2007, 15, 5047-5060.
137. Erion, M.D.; Reddy, K.R.; Boyer, S.H.; Matelich, M.C.; Gomez-Galeno, J.; Lemus, R.H.; Ugarkar, B.G.; Colby, T.J.; Schanzer, J.; Van Poelje, P.D. Design, synthesis, and characterization of a series of cytochrome P(450) 3a-activated prodrugs (hepdirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver. J. Am. Chem. Soc., 2004, 126, 5154-5163.
138. Erion, M.D.; van Poelje, P.D.; Mackenna, D.A.; Colby, T.J.; Mon-tag, A.C.; Fujitaki, J.M.; Linemeyer, D.L.; Bullough, D.A. Liver-targeted drug delivery using hepdirect prodrugs. J. Pharmacol. Exp. Ther., 2005, 312, 554-560.
139. Boyer, S.H.; Sun, Z.; Jiang, H.; Esterbrook, J.; Gomez-Galeno, J.E.; Craigo, W.; Reddy, K.R.; Ugarkar, B.G.; MacKenna, D.A.; Erion, M.D. Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-ß-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma. J. Med. Chem., 2006, 49, 7711-7720.
140. Erion, M.D.; Cable, E.E.; Ito, B.R.; Jiang, H.; Fujitaki, J.M.; Finn, P.D.; Zhang, B.H.; Hou, J.; Boyer, S.H.; van Poelje, P.D.; Line-meyer, D.L. Targeting thyroid hormone receptor-ß agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc. Natl. Acad. Sci. USA, 2007, 104, 15490-15495.
141. Hecker, S.J.; Reddy, K.R.; van Poelje, P.D.; Sun, Z.; Huang, W.; Varkhedkar, V.; Reddy, M.V.; Fujitaki, J.M.; Olsen, D.B.; Koeplinger, K.A.; Boyer, S.H.; Linemeyer, D.L.; MacCoss, M.; Erion, M.D. Liver-targeted prodrugs of 2'-C-methyladenosine for therapy of hepatitis c virus infection. J. Med. Chem., 2007, 50, 3891-3896.
142. Reddy, K.R.; Matelich, M.C.; Ugarkar, B.G.; Gomez-Galeno, J.E.; Dare, J.; Ollis, K.; Sun, Z.; Craigo, W.; Colby, T.J.; Fujitaki, J.M.; Boyer, S.H.; van Poelje, P.D.; Erion, M.D. Pradefovir: A prodrug that targets adefovir to the liver for the treatment of hepatitis B. J. Med. Chem., 2008, 51, 666-676.
143. Dando, T.; Plosker, G. Adefovir dipivoxil: a review of its use in chronic hepatitis B. Drugs, 2003, 63, 2215-2234.
144. Erion, M.D.; Bullough, D.A.; Lin, C.C.; Hong, Z. Hepdirect pro-drugs for targeting nucleotide-based antiviral drugs to the liver. Curr. Opin. Investig. Drugs, 2006, 7, 109-117.
145. Tillmann, H.L. Pradefovir, a liver-targeted prodrug of adefovir against hbv infection. Curr. Opin. Investig. Drugs, 2007, 8, 682-690.
146. nd Ed.; Class Publishing: London, 2002.
147. Benner, B.M. Benner & Rector's the Kidney. 7th Ed.; Vol. 1; Elsevier, Inc.: Philadelphia, 2004.
148. Haas, M.; Moolenaar, F.; Meijer, D.K.; de Zeeuw, D. Specific drug delivery to the kidney. Cardiovasc. Drugs Ther., 2002, 16, 489-496.
149. Wilk, S.; Mizoguchi, H.; Orlowski, M. T-Glutamyl dopa: A kidney-specific dopamine precursor. J. Pharmacol. Exp. Ther., 1978, 206, 227-232.
150. Barthelmebs, M.; Caillette, A.; Ehrhardt, J.D.; Velly, J.; Imbs, J.L. Metabolism and vascular effects of T-L-glutamyl-l-dopa on the isolated rat kidney. Kidney Int., 1990, 37, 1414-1422.
151. Drieman, J.C.; van Kan, F.J.; Thijssen, H.H.; van Essen, H.; Smits, J.F.; Struijker Boudier, H.A. Regional haemodynamic effects of dopamine and its prodrugs l-dopa and gludopa in the rat and in the glycerol-treated rat as a model for acute renal failure. Br. J. Pharmacol, 1994, 111, 1117-1122.
152. Lee, M.R. Five Years' experience with T-L-Glutamyl-L-Dopa: A relatively renally specific dopaminergic prodrug in man. J. Auton. Pharmacol, 1990, 10 (Suppl 1), s103-108.
153. Orlowski, M.; Mizoguchi, H.; Wilk, S. N-Acyl-r-glutamyl derivatives of sulfamethoxazole as models of kidney-selective prodrugs. J. Pharmacol. Exp. Ther. 1980, 212, 167-172.
154. Drieman, J.C.; Thijssen, H.H.; Struyker-Boudier, H.A. Renal selective N-Acetyl-r-glutamyl prodrugs. Ii. carrier-mediated transport and intracellular conversion as determinants in the renal selectivity of N-Acetyl-r-glutamyl sulfamethoxazole. J. Pharmacol. Exp. Ther., 1990, 252, 1255-1260.
155. Drieman, J.C.; Thijssen, H.H.; Zeegers, H.H.; Smits, J.F.; Struyker Boudier, H.A. Renal selective N-acetyl-r-glutamyl prodrugs: A study on the mechanism of activation of the renal vasodilator prodrug Cgp 22979. Br. J. Pharmacol, 1990, 99, 15-20.
156. Drieman, J.C.; Thijssen, H.H. Renal selective N-acetyl-L-r-glutamyl prodrugs. Iii. N-acetyl-L-r-glutamyl-4'-aminowarfarin is not targeted to the kidney but is selectively excreted into the bile. J. Pharmacol. Exp. Ther., 1991, 259, 766-771.
157. Drieman, J.C.; Thijssen, H.H.; Struyker-Boudier, H.A. Renal selective n-acetyl-l-y-glutamyl prodrugs: Studies on the selectivity of some model prodrugs. Br. J. Pharmacol, 1993, 108, 204-208.
158. Hwang, I.Y.; Elfarra, A.A. Cysteine S-conjugates may act as kidney-selective prodrugs: Formation of 6-mercaptopurine by the renal metabolism of S-(6-Purinyl)-L-cysteine. J. Pharmacol. Exp. Ther., 1989, 251, 448-454.
159. Hwang, I.Y.; Elfarra, A.A. Kidney-Selective prodrugs of 6-mercaptopurine: biochemical basis of the kidney selectivity of s-(6-purinyl)-l-cysteine and metabolism of new analogs in rats. J. Pharmacol. Exp. Ther., 1991, 258, 171-177.
160. Elfarra, A.A.; Duescher, R.J.; Hwang, I.Y.; Sicuri, A.R.; Nelson, J.A. Targeting 6-thioguanine to the kidney with S-(Guanin-6-Yl)-L-cysteine. J. Pharmacol. Exp. Ther., 1995, 274, 1298-1304.
161. Elfarra, A.A.; Hwang, I.Y. Targeting of 6-mercaptopurine to the kidneys. metabolism and kidney-selectivity of S-(6-Purinyl)-L-cysteine analogs in rats. Drug Metab. Dispos., 1993, 21, 841-845.
162. Andreadou, I.; Menge, W.M.; Commandeur, J.N.; Worthington, E.A.; Vermeulen, N.P. Synthesis of Novel se-substituted selenocys-teine derivatives as potential Kidney selective prodrugs of biologically active selenol compounds: evaluation of kinetics of ß-elimination reactions in rat renal cytosol. J. Med. Chem., 1996, 39, 2040-2046.
163. Commandeur, J.N.; Andreadou, I.; Rooseboom, M.; Out, M.; de Leur, L.J.; Groot, E.; Vermeulen, N.P. Bioactivation of selenocys-teine se-conjugates by a highly purified rat renal cysteine conjugate ß-lyase/glutamine transaminase K. J. Pharmacol. Exp. Ther., 2000, 294, 753-761.
164. Rooseboom, M.; Vermeulen, N.P.; Andreadou, I.; Commandeur, J.N. Evaluation of the kinetics of ß-elimination reactions of seleno-cysteine se-conjugates in human renal cytosol: Possible implications for the use as kidney selective prodrugs. J. Pharmacol. Exp. Ther., 2000, 294, 762-769.
165. Dove, A. Breaching the barrier. Nat. Biotechnol, 2008, 26, 1213-1215.
166. Risau, W.; Rubanyi, G.M., Eds. Morphogenesis of Endothelium. Endothelial Cell Research Series;Rubanyi, G.M.;Ed; Taylor & Francis Group: London, 2000.
167. Zhang, Y.; Miller, D.W., Pathways for Drug Delivery to the Central Nervous System. In Drug Delivery: Principles and Applications Wang, B.; Ed; John Wiley & Sons, Inc.: Hoboken, 2005.
168. Rautio, J.; Laine, K.; Gynther, M.; Savolainen, J. Prodrug approaches for Cns delivery. AAPS J., 2008, 10, 92-102.
169. Pavan, B.; Dalpiaz, A.; Ciliberti, N.; Biondi, C; Manfredini, S.; Vertuani, S. Progress in drug delivery to the central nervous system by the prodrug approach. Molecules, 2008, 13, 1035-1065.
170. Armstrong, S.C.; Cozza, K.L. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: Theory and clinical reality, part Ii. Psychosomatics, 2003, 44, 515-520.
171. Oldendorf, W.H.; Hyman, S.; Braun, L.; Oldendorf, S.Z. Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science, 1972, 178, 984-986.
172. Chen, Z.R.; Irvine, R.J.; Bochner, F.; Somogyi, A.A. Morphine formation from codeine in rat brain: A possible mechanism of codeine analgesia. Life Sci., 1990, 46, 1067-1074.
173. Lundquist, S.; Renftel, M.; Brillault, J.; Fenart, L.; Cecchelli, R.; Dehouck, M.P. Prediction of drug transport through the blood-brain barrier in vivo: A comparison between two in vitro cell models. Pharm. Res., 2002, 19, 976-981.
174. Pai, H.V.; Kommaddi, R.P.; Chinta, S.J.; Mori, T.; Boyd, M.R.; Ravindranath, V. A Frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502d7 that demethylates codeine to Morphine. J. Biol. Chem., 2004, 279, 27383-27389.
175. Bodor, N.; Farag, H.H.; Brewster, M.E. Site-specific, sustained release of drugs to the brain. Science, 1981, 214, 1370-1372.
176. Brewster, M.E.; Anderson, W.; Bodor, N. Brain, blood, and cerebrospinal fluid distribution of a zidovudine chemical delivery system in rabbits. J. Pharm. Sci., 1991, 80, 843-846.
177. Lupia, R.H.; Ferencz, N.; Lertora, J.J.; Aggarwal, S.K.; George, W.J.; Agrawal, K.C. Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue. Antimicrob. Agents Chemother., 1993, 37, 818-824.
178. Mizrachi, Y.; Rubinstein, A.; Harish, Z.; Biegon, A.; Anderson, W.R.; Brewster, M.E. Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system. AIDS, 1995, 9, 153-158.
179. Brewster, M.E.; Anderson, W.R.; Webb, A.I.; Pablo, L.M.; Me-insma, D.; Moreno, D.; Derendorf, H.; Bodor, N.; Pop, E. Evaluation of a brain-targeting zidovudine chemical delivery system in dogs. Antimicrob. Agents Chemother., 1997, 41, 122-128.
180. Tapfer, M.K.; Sebestyen, L.; Kurucz, I.; Horvath, K.; Szelenyi, I.; Bodor, N. New Evidence for the selective, long-lasting central effects of the brain-targeted estradiol, estredox. Pharmacol. Biochem. Behav., 2004, 77, 423-429.
181. Sziraki, I.; Horvath, K.; Bodor, N. Comparative evaluation of estredox, a brain-targeted estradiol delivery system versus traditional estrogen replacement therapy. Pharmazie, 2006, 61, 140-143.
182. Del Amo, E.M.; Urtti, A.; Yliperttula, M. Pharmacokinetic role of L-type amino acid transporters lat1 and lat2. Eur. J. Pharm. Sci., 2008, 35, 161-174.
183. Fernandez, C.; Nieto, O.; Fontenla, J.A.; Rivas, E.; de Ceballos, M.L.; Fernandez-Mayoralas, A. Synthesis of glycosyl derivatives as dopamine prodrugs: Interaction with glucose carrier glut-1. Org. Biomol. Chem., 2003, 1, 767-771.
184. Fernandez, C.; Nieto, O.; Rivas, E.; Montenegro, G.; Fontenla, J.A.; Fernandez-Mayoralas, A. Synthesis and biological studies of glycosyl dopamine derivatives as potential antiparkinsonian agents. Carbohydr. Res., 2000, 327, 353-365.
185. Bonina, F.; Puglia, C.; Rimoli, M.G.; Melisi, D.; Boatto, G.; Nieddu, M.; Calignano, A.; La Rana, G.; De Caprariis, P. Glycosyl derivatives of dopamine and l-dopa as anti-parkinson prodrugs: Synthesis, pharmacological activity and in vitro stability studies. J. Drug Target, 2003, 11, 25-36.
186. Engelhard, H.H. Gene therapy for brain tumors: The fundamentals. Surg. Neurol. 2000, 54, 3-9.
187. Illum, L. Transport of drugs from the nasal cavity to the central nervous system. Eur. J. Pharm. Sci., 2000, 11, 1-18.
188. Illum, L. Is Nose-to-brain transport of drugs in man a reality? J. Pharm. Pharmacol. 2004, 56, 3-17.
189. Koonin, E.V.; Senkevich, T.G.; Dolja, V.V. The ancient virus world and evolution of cells. Biol. Direct., 2006, 1, 29.
190. Mackman, R.L.; Zhang, L.; Prasad, V.; Boojamra, C.G.; Douglas, J.; Grant, D.; Hui, H.; Kim, C.U.; Laflamme, G.; Parrish, J.; Stoy-cheva, A.D.; Swaminathan, S.; Wang, K.; Cihlar, T. Synthesis, anti-hiv activity, and resistance profile of thymidine phosphono-methoxy nucleosides and their bisisopropyloxymethylcarbonyl (Bispoc) prodrugs. Bioorg. Med. Chem., 2007, 15, 5519-5528.
191. Rossi, L.; Serafini, S.; Franchetti, P.; Cappellacci, L.; Fraternale, A.; Casabianca, A.; Brandi, G.; Pierige, F.; Perno, C.F.; Balestra, E.; Benatti, U.; Millo, E.; Grifantini, M.; Magnani, M. Targeting Nucleotide Dimers Containing Antiviral Nucleosides. Curr. Med. Chem. Anti-Infect. Agents, 2005, 4, 37-54.
192. Elion, G.B.; Furman, P.A.; Fyfe, J.A.; de Miranda, P.; Beauchamp, L.; Schaeffer, H.J. Selectivity of action of an antiherpetic agent, 9-(2-Hydroxyethoxymethyl) guanine. Proc. Natl. Acad. Sci. USA, 1977, 74, 5716-5720.
193. Cai, T.B.; Lu, D.; Landerholm, M.; Wang, P.G. Sialated diazeni-umdiolate: A new sialidase-activated nitric oxide donor. Org. Lett., 2004, 6, 4203-4205.
194. Torre, D.; Pugliese, A.; Speranza, F. Role of nitric oxide in Hiv-1 infection: Friend or foe? Lancet Infect. Dis., 2002, 2, 273-280.