Targeted prodrugs in oral drug delivery: The modern molecular biopharmaceutical approach

Expert Opinion on Drug Delivery

Volumn 9, Issue 8, 2012, Pages 1001-1013

  Dahan, Arik ^a   Khamis, Mustafa ^b   Agbaria, Riad ^a   Karaman, Rafik ^b  

^a BEN GURION UNIVERSITY OF THE NEGEV   (Israel)

^b AL QUDS UNIVERSITY   (Palestine)

Author keywords

DFT and ab initio calculations; Membrane transporters; Molecular biopharmaceutics; Passive active intestinal permeability; Prodrug activation; Targeted prodrug approach

Indexed keywords

ACICLOVIR; ALENDRONIC ACID; AMINO ACID TRANSPORTER; BETA LACTAM ANTIBIOTIC; CARRIER PROTEIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; FLOXURIDINE; FOLATE TRANSPORTER; GABAPENTIN; GABAPENTIN ENACARBIL; GANCICLOVIR; GEMCITABINE; HYDROLASE; MELPHALAN; METFORMIN; METOPROLOL; MIDODRINE; MONOCARBOXYLATE TRANSPORTER; ORGANIC ANION TRANSPORTER; ORGANIC CATION TRANSPORTER; OSELTAMIVIR; PEPTIDE TRANSPORTER 1; PRODRUG; SODIUM DEPENDENT BILE ACID TRANSPORTER; SODIUM GLUCOSE COTRANSPORTER; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALACICLOVIR; VALACYCLOVIRASE; ZANAMIVIR; ZIDOVUDINE;

CHEMICAL MODIFICATION; DENSITY FUNCTIONAL THEORY; DRUG ABSORPTION; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG EFFICACY; DRUG HYDROLYSIS; DRUG PENETRATION; DRUG TRANSPORT; HUMAN; INFLUENZA A (H1N1); INTESTINE MUCOSA PERMEABILITY; NONHUMAN; REVIEW; SEASONAL INFLUENZA;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AGENTS; BIOLOGICAL TRANSPORT; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; MEMBRANE TRANSPORT PROTEINS; PHARMACEUTICAL PREPARATIONS; PRODRUGS;

EID: 84864273540     PISSN: 17425247     EISSN: 17447593     Source Type: Journal    
DOI: 10.1517/17425247.2012.697055     Document Type: Review

References (102)

1. Huttunen KM, Raunio H, Rautio J. Prodrugs - from serendipity to rational design. Pharmacol Rev 2011;63:750-71
2. Stella VJ. Prodrugs: Some thoughts and current issues. J Pharm Sci 2010;99:4755-65
3. Beaumont K, Webster R, Gardner I, Dack K. Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: Challenges to the discovery scientist. Curr Drug Metab 2003;4:461-85
4. Amidon GL, Leesman GD, Elliott RL. Improving intestinal absorption of water-insoluble compounds: A membrane metabolism strategy. J Pharm Sci 1980;69:1363-8
5. Fleisher D, Bong R, Stewart BH. Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs. Adv Drug Deliv Rev 1996;19:115-30
6. Stella VJ, Nti-Addae KW. Prodrug strategies to overcome poor water solubility. Adv Drug Deliv Rev 2007;59:677-94
7. Bernard T. Prodrugs: bridging pharmacodynamic/pharmacokinetic gaps. Curr Opin Chem Biol 2009;13:338-44
8. Ettmayer P, Amidon GL, Clement B, Testa B. Lessons learned from marketed and investigational prodrugs. J Med Chem 2004;47:2393-404
9. Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: Design and clinical applications. Nat Rev Drug Discov 2008;7:255-70
10. Han HK, Amidon GL. Targeted prodrug design to optimize drug delivery. AAPS PharmSci 2000;2:E6
11. Majumdar S, Duvvuri S, Mitra AK. Membrane transporter/receptor-targeted prodrug design: Strategies for human and veterinary drug development. Adv Drug Deliv Rev 2004;56:1437-52
12. Tamai I. Oral drug delivery utilizing intestinal OATP transporters. Adv Drug Deliv Rev 2012; In press
13. Jonker JW, Schinkel AH. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, nd 3 (SLC22A1-3). J Pharmacol Exp Ther 2004;308:2-9
14. Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: Structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 2007;24:1227-51
15. Balakrishnan A, Polli JE. Apical sodium dependent bile acid transporter (ASBT, SLC10A2): A potential prodrug target. Mol Pharm 2006;3:223-30
16. Cao X, Gibbs S, Fang L, et al. Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm Res 2006;23:1675-86
17. Tsuji A. Tissue selective drug delivery utilizing carrier-mediated transport systems. J Control Release 1999;62:239-44
18. Varma M, Ambler C, Ullah M, et al. Targeting intestinal transporters for optimizing oral drug absorption. Curr Drug Metab 2010;11:730-42
19. Anderson CMH, Grenade DS, Boll M, et al. H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat. Gastroenterology 2004;127:1410-22
20. Thwaites DT, Anderson CMH. The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol 2011;164:1802-16
21. Ganapathy ME, Ganapathy V. Amino acid transporter ATB0, + as a delivery system for drugs and prodrugs. Curr Drug Targets Immune Endocr Metab Disord 2005;5:357-64
22. Hatanaka T, Haramura M, Fei Y-J, et al. Transport of amino acid-based prodrugs by the Na+- and Cl- coupled amino acid transporter ATB0, + and expression of the transporter in tissues amenable for drug delivery. J Pharmacol Exp Ther 2004;308:1138-47
23. Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006;127:917-28
24. Zhao R, Diop-Bove N, Visentin M, Goldman ID. Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 2011;31:177-201
25. Bai JPF, Amidon GL. Structural specificity of mucosal-cell transport and metabolism of peptide drugs: Implication for oral peptide drug delivery. Pharm Res 1992;9:969-78
26. Brandsch M, Knutter I, Bosse-Doenecke E. Pharmaceutical and pharmacological importance of peptide transporters. J Pharm Pharmacol 2008;60:543-85
27. Kikuchi A, Tomoyasu T, Tanaka M, et al. Peptide derivation of poorly absorbable drug allows intestinal absorption via peptide transporter. J Pharm Sci 2009;98:1775-87
28. Lee VHL, Chu C, Mahlin ED, et al. Biopharmaceutics of transmucosal peptide and protein drug administration: Role of transport mechanisms with a focus on the involvement of PepT1. J Control Release 1999;62:129-40
29. Giacomini K, Huang S, Tweedie D, et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010;9:215-36
30. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y. Impact of drug transporter studies on drug discovery and development. Pharmacol Rev 2003;55:425-61
31. Shugarts S, Benet L. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res 2009;26:2039-54
32. Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: A review of fundamentals. J Clin Pharmacol 2002;42:620-43
33. Jappar D, Hu Y, Smith DE. Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and pept1 knockout mice. Drug Metab Dispos 2011;39:2250-7
34. Aoki FY, Doucette KE. Oseltamivir: A clinical and pharmacological perspective. Expert Opin Pharmacother 2001;2:1671-83
35. Le QM, Kiso M, Someya K, et al. Avian flu: Isolation of drug-resistant H5N1 virus. Nature 2005;437:1108-8
36. Cass L, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 1999;36:1-11
37. Varghese Gupta S, Gupta D, Sun J, et al. Enhancing the intestinal membrane permeability of zanamivir: A carrier mediated prodrug approach. Mol Pharm 2011;8:2358-67
38. Miller JM, Dahan A, Gupta D, et al. Enabling the intestinal absorption of highly polar antiviral agents: Ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir. Mol Pharm 2010;7:1223-34
39. Dawood F, Jain S, Finelli L, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-15
40. Landowski CP, Vig BS, Song X, Amidon GL. Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs. Mol Cancer Ther 2005;4:659-67
41. Tsume Y, Hilfinger J, Amidon G. Potential of amino acid/dipeptide monoester prodrugs of floxuridine in facilitating enhanced delivery of active drug to interior sites of tumors: A two-tier monolayer in vitro study. Pharm Res 2011;28:2575-88
42. Tsume Y, Hilfinger JM, Amidon GL. Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: Increased transporter affinity and metabolic stability. Mol Pharm 2008;5:717-27
43. Han H-K, de Vrueh RLA, Rhie JK, et al. 5¢-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res 1998;15:1154-9
44. Li F, Maag H, Alfredson T. Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J Pharm Sci 2008;97:1109-34
45. Mittal S, Song X, Vig BS, et al. Prolidase, a potential enzyme target for melanoma: Design of proline-containing dipeptide-like prodrugs. Mol Pharm 2005;2:37-46
46. Song X, Lorenzi PL, Landowski CP, et al. Amino acid ester prodrugs of the anticancer agent gemcitabine: Synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport. Mol Pharm 2005;2:157-67
47. Tsuda M, Terada T, Irie M, et al. Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives. J Pharmacol Exp Ther 2006;318:455-60
48. Ezra A, Hoffman A, Breuer E, et al. A peptide prodrug approach for improving bisphosphonate oral absorption. J Med Chem 2000;43:3641-52
49. Halestrap A, Meredith D. The SLC16 gene family - from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 2004;447:619-28
50. Cundy KC, Annamalai T, Bu L, et al. XP13512, a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol Exp Ther 2004;311:324-33
51. Cundy KC, Sastry S, Luo W, et al. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol 2008;48:1378-88
52. Cundy KC, Branch R, Chernov-Rogan T, et al. XP13512, a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther 2004;311:315-23
53. Tolle-Sander S, Lentz KA, Maeda DY, et al. Increased acyclovir oral bioavailability via a bile acid conjugate. Mol Pharm 2004;1:40-8
54. Rais R, Fletcher S, Polli JE. Synthesis and in vitro evaluation of gabapentin prodrugs that target the human apical sodium-dependent bile acid transporter (hASBT). J Pharm Sci 2011;100:1184-95
55. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413
56. Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: Provisional BCS classification of the world's top oral drugs. AAPS J 2009;11:740-6
57. Dahan A. Miller J.M. Hilfinger J.M. et al. High-permeability criterion for BCS classification: Segmental/pH dependent permeability considerations Mol. Pharm. 2010 7 1827-34.
58. Dahan A, Miller JM, Hilfinger JM, et al. High-permeability criterion for BCS classification: Segmental/pH dependent permeability considerations. Mol Pharm 2010;7:1827-1834
59. Sun D, Yu L, Hussain M, et al. In vitro testing of drug absorption for drug 'developability' assessment: Forming an interface between in vitro preclinical data and clinical outcome. Curr Opin Drug Discov Devel 2004;7:75-85
60. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3-26
61. Landowski CP, Lorenzi PL, Song X, Amidon GL. Nucleoside ester prodrug substrate specificity of liver carboxylesterase. J Pharmacol Exp Ther 2006;316:572-80
62. Liederer BM, Borchardt RT. Enzymes involved in the bioconversion of ester-based prodrugs. J Pharm Sci 2006;95:1177-95
63. Satoh T, Hosokawa M. The mammalian carboxylesterases: From molecules to functions. Annu Rev Pharmacol Toxicol 1998;38:257-88
64. Weller S, Blum M, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drug valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993;54:595-605
65. Balimane PV, Tamai I, Guo A, et al. Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem Biophys Res Commun 1998;250:246-51
66. Burnette TC, de Miranda P. Metabolic disposition of the acyclovir prodrug valacyclovir in the rat. Drug Metab Dispos 1994;22:60-4
67. de Miranda P, Burnette TC. Metabolic fate and pharmacokinetics of the acyclovir prodrug valacyclovir in cynomolgus monkeys. Drug Metab Dispos 1994;22:55-9
68. Soul-Lawton J, Seaber E, On N, et al. Absolute bioavailability and metabolic disposition of valacyclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother 1995;39:2759-64
69. Sinko PJ, Balimane PV. Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir. 1. Interactions with peptides, organic anions and organic cations in rats. Biopharm Drug Dispos 1998;19:209-17
70. Burnette TC, Harrington JA, Reardon JE, et al. Purification and characterization of a rat liver enzyme that hydrolyzes valacyclovir, the L-valyl ester prodrug of acyclovir. J Biol Chem 1995;270:15827-31
71. Kim I, Chu X-Y, Kim S, et al. Identification of a human valacyclovirase. J Biol Chem 2003;278:25348-56
72. Lai L, Xu Z, Zhou J, et al. Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase. J iol Chem 2008;283:9318-27
73. Gupta D, Gupta SV, Lee K-D, Amidon GL. Chemical and enzymatic stability of amino acid prodrugs containing methoxy, ethoxy and propylene glycol linkers. Mol Pharm 2009;6:1604-11
74. Kim I, Crippen GM, Amidon GL. Structure and specificity of a human valacyclovir activating enzyme: A homology model of BPHL. Mol Pharm 2004;1:434-46
75. Kim I, Song X, Vig BS, et al. A novel nucleoside prodrug-activating enzyme: Substrate specificity of biphenyl hydrolase-like protein. Mol Pharm 2004;1:117-27
76. Sun J, Dahan A, Walls ZF, et al. Specificity of a prodrug-activating enzyme hVACVase: The leaving group effect. Mol Pharm 2010;7:2362-8
77. Sun J, Miller JM, Beig A, et al. Mechanistic enhancement of the intestinal absorption of drugs containing the polar guanidino functionality. Expert Opin Drug Metab Toxicol 2011;7:313-23
78. Li W, Escarpe PA, Eisenberg EJ, et al. Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother 1998;42:647-53
79. Clement B, Mau S, Deters S, Havemeyer A. Hepatic, extrahepatic, microsomal, and mitochondrial activation of the N-hydroxylated prodrugs benzamidoxime, guanoxabenz, and Ro 48-3656 ([[1-[(2s)-2-[[4-[(hydroxyamino) iminomethyl]benzoyl]amino]-1- oxopropyl]-4-piperidinyl]oxy]-acetic acid). Drug Metab Dispos 2005;33:1740-7
80. Huttunen KM, Mannila A, Laine K, et al. The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption. J Med Chem 2009;52:4142-8
81. Maryanoff BE, McComsey DF, Costanzo MJ, et al. Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa. Chem Biol Drug Des 2006;68:29-36
82. Saulnier MG, Frennesson DB, Deshpande MS, et al. An efficient method for the synthesis of guanidino prodrugs. Bioorg Med Chem Lett 1994;4:1985-90
83. Sun J, Dahan A, Amidon GL. Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: A double-targeted prodrug approach. J Med Chem 2010;53:624-32
84. Dahan A, Duvdevani R, Dvir E, et al. A novel mechanism for oral controlled release of drugs by continuous degradation of a phospholipid prodrug along the intestine: In-vivo and in-vitro evaluation of an indomethacin-lecithin conjugate. J Control Release 007;119:86-93
85. Dahan A, Duvdevani R, Shapiro I, et al. The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration. J Control Release 2008;126:1-9
86. Dahan A, Hoffman A. Mode of administration-dependent brain uptake of indomethacin: Sustained systemic input increases brain influx. Drug Metab Dispos 2007;35:321-4
87. Dvir E, Elman A, Simmons D, et al. DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and Alzheimer's disease therapy. CNS Drug Rev 2007;13:260-77
88. Dvir E, Friedman JE, Lee JY, et al. A novel phospholipid derivative of indomethacin, DP-155, shows superior safety and similar efficacy in reducing brain amyloid beta in an Alzheimer's disease model. J Pharmacol Exp Ther 2006;318:1248-56
89. Kurz M, Scriba GKE. Drug-phospholipid conjugates as potential prodrugs: Synthesis, characterization, and degradation by pancreatic phospholipase A2. Chem Phys Lipids 2000;107:143-57
90. Reddy M, Erion M. Free energy calculations in rational drug design. Kluwer/Plenum Press; New York: 2001
91. Schrodinger E. Quantisierung als eigenwertproblem. Ann Phys 1926;79:361-76
92. Dewar MJS, Thiel W. Ground states of molecules. 38. The MNDO method. Approximations and parameters. J Am Chem Soc 1977;99:4899-907
93. Parr R, Yang W. Density functional theory of atoms and molecules. Oxford University Press; Oxford: 1989
94. Burkert U, Allinger NL. Molecular mechanics. In: ACS Monograph 177. American Chemical Society; Washington DC:1982. p. 339
95. Karaman R. Analysis of Menger's 'spatiotemporal hypothesis'. Tetrahedron Lett 2008;49:5998-6002
96. Karaman R. Cleavage of Menger's aliphatic amide: A model for peptidase enzyme solely explained by proximity orientation in intramolecular proton transfer. J Mol Struct 2009;910:27-33
97. Karaman R. The efficiency of proton transfer in Kirby's enzyme model, a computational approach. Tetrahedron Lett 2010;51:2130-5
98. Karaman R, Hallak H. Computer-assisted design of pro-drugs for antimalarial atovaquone. Chem Biol Drug Des 2010;76:350-60
99. Karaman R. Analyzing the efficiency in intramolecular amide hydrolysis of Kirby's N-alkylmaleamic acids - a computational approach. Comput Theor Chem 2011;974:133-42
100. Hejaz H, Karaman R, Khamis M. Computer-assisted design for paracetamol masking bitter taste prodrugs. J Mol Model 2012;18:103-14
101. Karaman R. Computational-aided design for dopamine prodrugs based on novel chemical approach. Chem Biol Drug Des 2011;78:853-63
102. Karaman R, Dajani KK, Qtait A, Khamis M. Prodrugs of acyclovir - a computational approach. Chem Biol Drug Des 2012;79:819-34