Prodrugs pp 157-215 | Cite as

Overcoming Poor Aqueous Solubility of Drugs for Oral Delivery

  • Tycho Heimbach
  • David Fleisher
  • Amal Kaddoumi
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)

Abstract

It is estimated that 40% of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble, i.e., these compounds have an aqueous solubility less than 10 µM (5 µg/mL for a compound with a molecular weight of 500) (Lipinski, 2002, 2004). When these poorly soluble NCEs are further advanced in discovery and ultimately brought into development they are often plagued by incomplete absorption and low, erratic bioavailability. There are a limited number of options available to drug discovery scientists to enhance the solubility of a compound by conventional formulation approaches. These include the identification and selection of stable pharmaceutical salts (Stahl, 2003). However, salt formation requires an ionizable group and, therefore, this is not a viable option for neutral compounds or those with ionization constants that do not fall within the physiological range. Other common approaches are reducing solid particle size by micronization, such as milling or the formation of nanosuspensions (Müller et al., 2001), the use of complexation agents such as cyclodextrins (Rao and Stella, 2003), or the use of solubilizing excipients (Strickley, 2004). While these solubilization techniques often lead to significant improvement in systemic exposure when availability is solubility- or dissolution-rate limited, conventional formulation approaches are not always successful and an alternate strategy is required.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Amidon GL. Drug Derivatization as a Means of Solubilization: Physiochemical and Biochemical Strategies. New York: Marcel Dekker. 1981. p 183–208Google Scholar
  2. Amidon GL, Leesman GD, and Elliott RL. Improving Intestinal Absorption of Water-Insoluble Compounds: A Membrane Metabolism Strategy. J Pharm Sci 1980; 69:1363–1368PubMedGoogle Scholar
  3. Amidon GL, Stewart BH, and Pogany S. Improving the Intestinal Mucosal Cell Uptake of Water Insoluble Compounds. J Control Release 1985; 2:13–26Google Scholar
  4. Amidon GL, Lennernaes H, Shah VP, and 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; 12:413–420PubMedGoogle Scholar
  5. Anand BS, Katragadda S, and Mitra AK. Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir after Oral Administration: Intestinal Absorption and Liver Metabolism. J Pharmacol Exp Ther 2004; 311:659–667PubMedGoogle Scholar
  6. Anderson PL. Pharmacologic Perspectives for Once-Daily Antiretroviral Therapy. Ann Pharmacother 2004; 38:1924–1934PubMedGoogle Scholar
  7. Annaert P, Tukker JJ, Van Gelder J, Naesens L, De Clercq E, Van Den Mooter G, Kinget R, and Augustijns P. In Vitro, Ex Vivo, and In Situ Intestinal Absorption Characteristics of the Antiviral Ester Prodrug Adefovir Dipivoxil. J Pharm Sci 2000; 89:1054–1062PubMedGoogle Scholar
  8. Aoyama H, Tominaga T, and Abe O. Early Phase II Study of Tat-59 in Patients with Advanced or Recurrent Breast Cancer—A Multicenter Dose Finding Study. Gan to Kagaku Ryoho 1998; 25:853–865PubMedGoogle Scholar
  9. Arky R. Physicians’ Desk Reference. Montvale, N. J.: Medical Economics Company. 2000Google Scholar
  10. Bai JP, Hu M, Subramanian P, Mosberg HI, and Amidon GL. Utilization of Peptide Carrier System to Improve Intestinal Absorption: Targeting Prolidase as a Prodrug-Converting Enzyme. J Pharm Sci 1992; 81:113–116PubMedGoogle Scholar
  11. Baker WR, Cai S, Dimitroff M, Fang L, Huh KK, Ryckman DR, Shang X, Shawar RM, and Therrien JH. A Prodrug Approach toward the Development of Water Soluble Fluoroquinolones and Structure-Activity Relationships of Quinoline-3-Carboxylic Acids. J Med Chem 2004; 47:4693–4709PubMedGoogle Scholar
  12. Banaszczyk MG, Carlo AT, Millan V, Lindsey A, Moss R, Carlo DJ, and Hendler SS. Propofol Phosphate, a Water-Soluble Propofol Prodrug: In Vivo Evaluation. Anesth Analg 2002; 95:1285–1292PubMedGoogle Scholar
  13. Beaumont K, Webster R, Gardner I, and Dack K. Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist. Curr Drug Metab 2003; 4:461–485PubMedGoogle Scholar
  14. Becker S, and Thornton L. Fosamprenavir: Advancing HIV Protease Inhibitor Treatment Options. Expert Opin Pharmacother 2004; 5:1995–2005PubMedGoogle Scholar
  15. Bentley A, Butters M, Green SP, Learmonth WJ, MacRae JA, Morland MC, O’Connor G, and Skuse J. The Discovery and Process Development of a Commercial Route to a Water Soluble Prodrug, Fosfluconazole. Org Process Res Dev 2002; 6:109–112Google Scholar
  16. Bergenheim AT, and Henriksson R. Pharmacokinetics and Pharmacodynamics of Estramustine Phosphate. Clin Pharmacokinet 1998; 34:163–172PubMedGoogle Scholar
  17. Bodanszky M, and Kwei JZ. Side Reactions in Peptide Synthesis. VII. Sequence Dependence in the Formation of Aminosuccinyl Derivatives from Beta-Benzyl-Aspartyl Peptides. Int J Pept Protein Res 1978; 12:69–74PubMedCrossRefGoogle Scholar
  18. Boogaerts MA, Van Hoof A, Catovsky D, Kovacs M, Montillo M, Zinzani PL, Binet JL, Feremans W, Marcus R, Bosch F, Verhoef G, and Klein M. Activity of Oral Fludarabine Phosphate in Previously Treated Chronic Lymphocytic Leukemia. J Clin Oncol 2001; 19:4252–4258PubMedGoogle Scholar
  19. Brockman RW, Schabel FM, Jr., and Montgomery JA. Biologic Activity of 9-B-DArabinofuranosyl-2-Fluoroadenine, a Metabolically Stable Analog of 9-B-DArabinofuranosyladenine. Biochem Pharmacol 1977; 26:2193–2196PubMedGoogle Scholar
  20. Burstein AH, Cox D, Mistry B, and Eddington N. Phenytoin Pharmacokinetics Following Oral Administration of Phenytoin Suspension and Fosphenytoin Solution to Rats. Epilepsy Res 1999; 34:129–133PubMedGoogle Scholar
  21. Caiolfa VR, Zamai M, Fiorino A, Frigerio E, Pellizzoni C, d’Argy R, Ghiglieri A, Castelli MG, Farao M, Pesenti E, Gigli M, Angelucci F, and Suarato A. Polymer-Bound Camptothecin: Initial Biodistribution and Antitumour Activity Studies. J Control Release 2000; 65:105–119PubMedGoogle Scholar
  22. Chan OH, Schmid HL, Stilgenbauer LA, Howson W, Horwell DC, and Stewart BH. Evaluation of a Targeted Prodrug Strategy of Enhance Oral Absorption of Poorly Water-Soluble Compounds. Pharm Res 1998; 15:1012–1018PubMedGoogle Scholar
  23. Chapman ™, Plosker GL, and Perry CM. Fosamprenavir: A Review of Its Use in the Management of Antiretroviral Therapy-Naive Patients with HIV Infection. Drugs 2004; 64:2101–2124PubMedGoogle Scholar
  24. Cho H, and Chung Y. Water Soluble Cyclosporine Monomethoxy Poly(Ethyleneglycol) Conjugates as Potential Prodrugs. Arch Pharm Res 2004; 27:662–669PubMedCrossRefGoogle Scholar
  25. Cho MJ, Kurtz RR, Lewis C, Machkovech SM, and Houser DJ. Metronidazole Phosphate—A Water-Soluble Prodrug for Parenteral Solutions of Metronidazole. J Pharm Sci 1982; 71:410–414PubMedGoogle Scholar
  26. Choi J-S, and Jo B-W. Enhanced Paclitaxel Bioavailability after Oral Administration of Pegylated Paclitaxel Prodrug for Oral Delivery in Rats. Int J Pharm 2004; 280:221–227PubMedGoogle Scholar
  27. Choi J-S, Jo B-W, and Kim Y-C. Enhanced Paclitaxel Bioavailability after Oral Administration of Paclitaxel or Prodrug to Rats Pretreated with Quercetin. Eur J Pharm Biopharm 2004; 57:313–318PubMedGoogle Scholar
  28. Chong BS, and Mersfelder TL. Entacapone. Ann Pharmacother 2000; 34:1056–1065PubMedGoogle Scholar
  29. Corbett AH, and Kashuba ADM. Fosamprenavir. Vertex Pharmaceuticals/GlaxoSmithKline. Curr Opin Invest Drugs 2002; 3:384–390Google Scholar
  30. Cundy KC, Annamalai T, Bu L, de Vera J, Estrela J, Luo W, Shirsat P, Torneros A, Yao F, Zou J, Barrett RW, and Gallop MA. 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; 311:324–333PubMedGoogle Scholar
  31. Davies NM, and Watson MS. Clinical Pharmacokinetics of Sulindac. A Dynamic Old Drug. Clin Pharmacokin 1997; 32:437–459Google Scholar
  32. de Jong RS, Mulder NH, Uges DR, Kaul S, Winograd B, Sleijfer D, Groen HJ, Willemse PH, van der Graaf WT, and de Vries EG. Randomized Comparison of Etoposide Pharmacokinetics after Oral Etoposide Phosphate and Oral Etoposide. Br J Cancer 1997; 75:1660–1666PubMedGoogle Scholar
  33. D’Emanuele A, Jevprasesphant R, Penny J, and Attwood D. The Use of a Dendrimer-Propranolol Prodrug to Bypass Efflux Transporters and Enhance Oral Bioavailability. J Control Release 2004; 95:447–453PubMedGoogle Scholar
  34. Dubowchik GM, and Firestone RA. Cathepsin B-Sensitive Dipeptide Prodrugs. 1. A Model Study of Structural Requirements for Efficient Release of Doxorubicin. Bioorg Med Chem Lett 1998; 8:3341–3346PubMedGoogle Scholar
  35. Duggan DE. Sulindac: Therapeutic Implications of the Prodrug/Pharmacophore Equilibrium. Drug Metabol Rev 1981; 12:325–337Google Scholar
  36. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan L-B, Yasuda K, Shepard RL, Winter MA, Schuetz JD, Wikel JH, and Wrighton SA. Three-Dimensional Quantitative Structure-Activity Relationships of Inhibitors of P-Glycoprotein. Mol Pharmacol 2002; 61:964–973PubMedGoogle Scholar
  37. Ellis JM, Ross JW, and Coleman CI. Fosamprenavir: A Novel Protease Inhibitor and Prodrug of Amprenavir. Formulary 2004; 39:151–154, 157–160Google Scholar
  38. Engle MJ, Mahmood A, and Alpers DH. Regulation of Surfactant-Like Particle Secretion by Caco-2 Cells. Biochim Biophys Acta 2001; 1511:369–380PubMedGoogle Scholar
  39. Ettmayer P, Amidon GL, Clement B, and Testa B. Lessons Learned from Marketed and Investigational Prodrugs. J Med Chem 2004; 47:2393–2404PubMedGoogle Scholar
  40. Falcoz C, Jenkins JM, Bye C, Hardman TC, Kenney KB, Studenberg S, Fuder H, and Prince WT. Pharmacokinetics of Gw433908, a Prodrug of Amprenavir, in Healthy Male Volunteers. J Clin Pharmacol 2002; 42:887–898PubMedGoogle Scholar
  41. Feng X, Yuan Y, and Wu J. Synthesis and Evaluation of Water-Soluble Paclitaxel Prodrugs. Bioorg Med Chem Lett 2002; 12:3301–3303PubMedGoogle Scholar
  42. Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, Baker J, and Kerr DJ. Phase I Clinical Trial of the Flavonoid Quercetin: Pharmacokinetics and Evidence for In Vivo Tyrosine Kinase Inhibition. Clin Cancer Res 1996; 2:659–668PubMedGoogle Scholar
  43. Fischer PM. Diketopiperazines in Peptide and Combinatorial Chemistry. J Pept Sci 2003; 9:9–35PubMedGoogle Scholar
  44. Fleckenstein L, Swynnerton NF, Ludden TM, and Mangold DJ. Bioavailability and Newer Methods of Delivery of Phosphorothioate Radioprotectors. Pharmacol Ther 1988; 39:203–212PubMedGoogle Scholar
  45. Fleisher D, Stewart BH, and Amidon GL. Design of Prodrugs for Improved Gastrointestinal Absorption by Intestinal Enzyme Targeting. Methods Enzymol 1985; 112:360–381PubMedCrossRefGoogle Scholar
  46. Fleisher D, Johnson KC, Stewart BH, and Amidon GL. Oral Absorption of 21-Corticosteroid Esters: A Function of Aqueous Stability and Intestinal Enzyme Activity and Distribution. J Pharm Sci 1986; 75:934–939PubMedGoogle Scholar
  47. Fleisher D, Bong R, and Stewart BH. Improved Oral Drug Delivery: Solubility Limitations Overcome by the Use of Prodrugs. Adv Drug Del Rev 1996; 19:115–130Google Scholar
  48. Flynn GL, and Lamb DJ. Factors Influencing Solvolysis of Corticosteroid-21-Phosphate Esters. J Pharm Sci 1970; 59:1433–1438PubMedGoogle Scholar
  49. Foran JM, and et al. Dose Dependent Increase of the Systemic 2F-Ara-a Exposure Following Single Oral Doses of 50, 70 and 90 mg Fludarabine. Blood 1997; 90 (Suppl. 1, Pt.1,327A):1574–1579Google Scholar
  50. Foran JM, Oscier D, Orchard J, Johnson SA, Tighe M, Cullen MH, De Takats PG, Kraus C, Klein M, and Lister TA. Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients with “Low-Grade” Non-Hodgkin’s Lymphoma and B-Cell Chronic Lymphocytic Leukemia. J Clin Oncol 1999; 17:1574–1579PubMedGoogle Scholar
  51. Forsberg M, Savolainen J, Jarvinen T, Leppänen J, Gynther J, and Mannisto PT. Pharmacodynamic Response of Entacapone in Rats after Administration of Entacapone Formulations and Prodrugs with Varying Bioavailabilities. Pharmacol Toxicol 2002; 90:327–332PubMedGoogle Scholar
  52. Furfine ES, Baker C, Boehlert C, Dahl R, Good S, Huang L, Kenney K, Klein R, Kutz S, Patrick M, Reynolds D, Salisbury J, and Spaltenstein A. 39th ICAAC, San Francisco, CA, 1999Google Scholar
  53. Furfine ES, Baker CT, Hale MR, Reynolds DJ, Salisbury JA, Searle AD, Studenberg SD, Todd D, Tung RD, and Spaltenstein A. Preclinical Pharmacology and Pharmacokinetics of Gw433908, a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir. Antimicrob Agents Chemother 2004; 48:791–798PubMedGoogle Scholar
  54. Gingrich DE, Reddy DR, Iqbal MA, Singh J, Aimone LD, Angeles TS, Albom M, Yang S, Ator MA, Meyer SL, Robinson C, Ruggeri BA, Dionne CA, Vaught JL, Mallamo JP, and Hudkins RL. A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Structure-Activity Relationships for a Series of 9 Alkoxymethyl 12 (3 Hydroxypropyl)Indeno[2,1-a]-Pyrrolo[3,4-C]Carbazole-5-Ones and the Identification of Cep 5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate Cep-7055. J Med Chem 2003; 46:5375–5388PubMedGoogle Scholar
  55. Goolcharran C, and Borchardt RT. Kinetics of Diketopiperazine Formation Using Model Peptides. J Pharm Sci 1998; 87:283–288PubMedGoogle Scholar
  56. Greco FA, and Hainsworth JD. Clinical Studies with Etoposide Phosphate. Semin Oncol 1996; 23(6 Suppl 13):45–50PubMedGoogle Scholar
  57. Greenwald RB, Pendri A, and Bolikal D. Highly Water Soluble Taxol Derivatives. 7 Polyethylene Glycol Carbamates and Carbonates. J Org Chem 1995; 60:331–336Google Scholar
  58. Greenwald RB, Gilbert CW, Pendri A, Conover CD, Xia J, and Martinez A. Drug Delivery Systems: Water Soluble Taxol 2′-Poly(Ethylene Glycol) Ester Prodrugs-Design and In Vivo Effectiveness. J Med Chem 1996; 39:424–431PubMedGoogle Scholar
  59. Greenwald RB, Pendri A, Conover CD, Zhao H, Choe YH, Martinez A, Shum K, and Guan S. Drug Delivery Systems Employing 1,4-or 1,6-Elimination: Poly(Ethylene Glycol) Prodrugs of Amine-Containing Compounds. J Med Chem 1999; 42:3657–3667PubMedGoogle Scholar
  60. Greenwald RB, Choe YH, Conover CD, Shum K, Wu D, and Royzen M. Drug Delivery Systems Based on Trimethyl Lock Lactonization: Poly(Ethylene Glycol) Prodrugs of Amino-Containing Compounds. J Med Chem 2000; 43:475–487PubMedGoogle Scholar
  61. Greenwald RB, Choe YH, McGuire J, and Conover CD. Effective Drug Delivery by Pegylated Drug Conjugates. Adv Drug Deliv Rev 2003; 55:217–250PubMedGoogle Scholar
  62. Greenwald RB, Zhao H, Yang K, Reddy P, and Martinez A. A New Aliphatic Amino Prodrug System for the Delivery of Small Molecules and Proteins Utilizing Novel PEG Derivatives. J Med Chem 2004; 47:726–734PubMedGoogle Scholar
  63. Grever M, Leiby J, Kraut E, Metz E, Neidhart J, Balcerzak S, and Malspeis L. A Comprehensive Phase I and II Clinical Investigation of Fludarabine Phosphate. Semin Oncol 1990; 17(5 Suppl 8):39–48PubMedGoogle Scholar
  64. Grosios K, Holwell SE, McGown AT, Pettit GR, and Bibby MC. In Vivo and In Vitro Evaluation of Combretastatin a-4 and Its Sodium Phosphate Prodrug. Br J Cancer 1999; 81:1318–1327PubMedGoogle Scholar
  65. Gugler R, Leschik M, and Dengler HJ. Disposition of Quercetin in Man after Single Oral and Intravenous Doses. Eur J Clin Pharmacol 1975; 9:229–234PubMedGoogle Scholar
  66. Guiotto A, Canevari M, Orsolini P, Lavanchy O, Deuschel C, Kaneda N, Kurita A, Matsuzaki T, Yaegashi T, Sawada S, and Veronese FM. Synthesis, Characterization, and Preliminary In Vivo Tests of New Poly(Ethylene Glycol) Conjugates of the Antitumor Agent 10 Amino 7 Ethylcamptothecin. J Med Chem 2004; 47:1280–1289PubMedGoogle Scholar
  67. Gunnarsson PO, Davidsson T, Andersson SB, Backman C, and Johansson SA. Impairment of Estramustine Phosphate Absorption by Concurrent Intake of Milk and Food. Eur J Clin Pharmacol 1990; 38:189–193PubMedGoogle Scholar
  68. Hamada Y, Ohtake J, Sohma Y, Kimura T, Hayashi Y, and Kiso Y. New Water-Soluble Prodrugs of HIV Protease Inhibitors Based on O→N Intramolecular Acyl Migration. Bioorg Med Chem 2002; 10:4155–4167PubMedGoogle Scholar
  69. Hamada Y, Matsumoto H, Kimura T, Hayashi Y, and Kiso Y. Effect of the Acyl Groups on O→N Acyl Migration in the Water-Soluble Prodrugs of HIV-1 Protease Inhibitor. Bioorg Med Chem Lett 2003; 13:2727–2730PubMedGoogle Scholar
  70. Hamada Y, Matsumoto H, Yamaguchi S, Kimura T, Hayashi Y, and Kiso Y. Water-Soluble Prodrugs of Dipeptide HIV Protease Inhibitors Based on O→N Intramolecular Acyl Migration: Design, Synthesis and Kinetic Study. Bioorg Med Chem 2004; 12:159–170PubMedGoogle Scholar
  71. Hamel AR, Hubler F, Carrupt A, Wenger RM, and Mutter M. Cyclosporin A Prodrugs: Design, Synthesis and Biophysical Properties. J Peptide Res 2004; 63:147–154Google Scholar
  72. Hanson BA, Schowen RL, and Stella VJ. A Mechanistic and Kinetic Study of the E-Ring Hydrolysis and Lactonization of a Novel Phosphoryloxymethyl Prodrug of Camptothecin. Pharm Res 2003; 20:1031–1038PubMedGoogle Scholar
  73. Hayashi Y, Skwarczynski M, Hamada Y, Sohma Y, Kimura T, and Kiso Y. A Novel Approach of Water Soluble Paclitaxel Prodrug with No Auxiliary and No Byproduct: Design and Synthesis of Isotaxel. J Med Chem 2003a; 46:3782–3784PubMedGoogle Scholar
  74. Hayashi Y, Skwarczynski M, Hamada Y, Sohma Y, Kimura T, and Kiso Y. Development of New Water-Soluble Prodrugs Based on Intramolecular Nucleophilic Reactions in Peptide Chemistry. Pept Sci 2003b; 40:73–76Google Scholar
  75. Heikkinen H, Saraheimo M, Antila S, Ottoila P, and Pentikainen PJ. Pharmacokinetics of Entacapone, a Peripherally Acting Catechol-O-Methyltransferase Inhibitor, in Man. A Study Using a Stable Isotope Technique. Eur J Clin Pharmacol 2001; 56:821–826PubMedGoogle Scholar
  76. Heimbach T. Oral Phosphate Prodrugs: Absorption Rate Limit Considerations. Ph.D. Thesis. Ann Arbor: University of Michigan. 2003. 198 ppGoogle Scholar
  77. Heimbach T, Oh D-M, Li LY, Rodriguez-Hornedo N, Garcia G, and Fleisher D. Enzyme-Mediated Precipitation of Parent Drugs from Their Phosphate Prodrugs. Int J Pharm 2003a; 261:81–92PubMedGoogle Scholar
  78. Heimbach T, Oh D-M, Li LY, Forsberg M, Leppänen J, Y. M, Flynn G, and Fleisher D. Absorption Rate Limit Considerations for Oral Phosphate Prodrugs. Pharm Res 2003b; 20:848–856PubMedGoogle Scholar
  79. Henchcliffe C, and Waters C. Entacapone in the Management of Parkinson’s Disease. Expert Opin Pharmacother 2002; 3:957–963PubMedGoogle Scholar
  80. Hidalgo IJ, Raub TJ, and Borchardt RT. Characterization of the Human Colon Carcinoma Cell Line (Caco-2) as a Model System for Intestinal Epithelial Permeability. Gastroenterol 1989; 96:736–749Google Scholar
  81. Hill SA, Toze GM, Pettit GR, and Chaplin DJ. Preclinical Evaluation of the Antitumour Activity of the Novel Vascular Targeting Agent Oxi 4503. Anticancer Res 2002; 22:1453–1458PubMedGoogle Scholar
  82. Ho NFH, Park JY, Morozowich W, and Higuchi W. Physical Model Approach to the Design of Drugs with Improved Intestinal Absorption. In: Roche EB, editor Design of Biopharmaceutical Properties through Prodrugs and Analogs. Washington, DC: American Pharmaceutical Association. 1977. 136–227Google Scholar
  83. Hoerter D, and Dressman JB. Influence of Physicochemical Properties on Dissolution of Drugs in the Gastrointestinal Tract. Adv Drug Deliv Rev 1997; 25:3–14Google Scholar
  84. Hooftman G, Herman S, and Schacht E. Poly(Ethylene Glycol)s with Reactive End groups. II. Practical Consideration for the Preparation of Protein-PEG Conjugates. J Bioact Compat Polymers 1996; 11:135–159Google Scholar
  85. Hook RH, Eastwood CJ, Jr., and Wright GJ. The Objective and Timing of Drug Disposition Studies, Appendix II. Plasma Concentrations of Oxyphenbutazone in Dogs Given Oxyphenbutazone or the Calcium or Sodium Salts of Its Phosphate Ester. Drug Metab Rev 1975; 4:249–265PubMedGoogle Scholar
  86. Humberstone AJ, Porter CJ, and Charman WN. A Physicochemical Basis for the Effect of Food on the Absolute Oral Bioavailability of Halofantrine. J Pharm Sci 1996; 85:525–529PubMedGoogle Scholar
  87. Kakeya N, Nishizawa S, Nishimura K, Yoshimi A, Tamaki S, Mori T, and Kitao K. KY-109, a New Bifunctional Prodrug of a Cephalosporin. Chemistry, Physicochemical and Biological Properties. J Antibiotics 1985; 38:380–389Google Scholar
  88. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernaes H, Hussain AS, Junginger HE, Stavchansky SA, Midha KK, Shah VP, and Amidon GL. Molecular Properties of Who Essential Drugs and Provisional Biopharmaceutical Classification. Mol Pharm 2004; 1:85–96PubMedGoogle Scholar
  89. Kearney AS. Evaluation of the Pharmaceutical Potential of Phosphate Ester Prodrugs. Ph.D. Thesis. Kansas: University of Kansas. 1990Google Scholar
  90. Kearney AS, and Stella VJ. Hydrolysis of Pharmaceutically Relevant Phosphate Monoester Monoanions: Correlation to an Established Structure-Reactivity Relationship. J Pharm Sci 1993; 82:69–72PubMedGoogle Scholar
  91. Kim H, Kumari P, Lin C-C, and Nomeir AA. Simultaneous High-Performance Liquid Chromatographic Determination of SCH 59884 (Phosphate Ester Prodrug of SCH 56592), SCH 207962 and SCH 56592 in Dog Plasma. J Pharm Biomed Anal 2002; 27:295–303PubMedGoogle Scholar
  92. Kiso Y, Matsumoto H, Yamaguchi S, and Kimura T. Design of Small Peptidomimetic HIV-1 Protease Inhibitors and Prodrug Forms. Lett Pept Sci 1999a; 6:275–281Google Scholar
  93. Kiso Y, Matsumoto H, Yamaguchi S, and Kimura T. Design of Small Peptidomimetic HIV-1 Protease Inhibitors and Prodrug Forms. Lett Peptide Sci 1999b; 6:275–281Google Scholar
  94. Kopecek J, and Duncan R. Targetable Polymeric Prodrugs. J Control Release 1987; 6:315–327Google Scholar
  95. Krise JP, and Stella VJ. Prodrugs of Phosphates, Phosphonates, and Phosphinates. Adv Drug Deliv Rev 1996; 19:287–310Google Scholar
  96. Krise JP, Zygmunt J, Georg GI, and Stella VJ. Novel Prodrug Approach for Tertiary Amines: Synthesis and Preliminary Evaluation of N-Phosphonooxymethyl Prodrugs. J Med Chem 1999a; 42:3094–3100PubMedGoogle Scholar
  97. Krise JP, Charman WN, Charman SA, and Stella VJ. A Novel Prodrug Approach for Tertiary Amines. 3. In Vivo Evaluation of Two N-Phosphonooxymethyl Prodrugs in Rats and Dogs. J Pharm Sci 1999b; 88:928–932PubMedGoogle Scholar
  98. Krise JP, Narisawa S, and Stella VJ. A Novel Prodrug Approach for Tertiary Amines. 2. Physicochemical and In Vitro Enzymatic Evaluation of Selected N-Phosphonooxymethyl Prodrugs. J Pharm Sci 1999c; 88:922–927PubMedGoogle Scholar
  99. Kusui Y, Rimkus KH, and Takasugi M. Physicochemical Properties and Stability of Fludara (Fludarabine Phosphate). Kagaku Ryoho No Ryoiki 2000; 16:1341–1343Google Scholar
  100. Kwon Y. Handbook of Essential Pharmacokinetics, Pharmacokinetics, and Drug Metabolism for Industrial Scientists: Kluwer Academic/Plenum Publishers. 2001Google Scholar
  101. Lai CM, Moore P, Matier WL, and Quon CY. Comparative Pharmacokinetics and Bioavailability of Phenytoin after Oral Phenytoin Sodium Capsule and IM Injection and Oral Capsule of a Prodrug of Phenytoin, Acc-9653, in Dogs. Pharm Res 1987; 2:S118Google Scholar
  102. Lee MG, and Chiou WL. Evaluation of Potential Causes for the Incomplete Bioavailability of Furosemide: Gastric First-Pass Metabolism. J Pharmacokinet Biopharm 1983; 11:623–640PubMedGoogle Scholar
  103. Leppanen J, Savolainen J, Nevalainen T, Forsberg M, Huuskonen J, Taipale H, Gynther J, Mannisto PT, and Jarvinen T. Synthesis and in-Vitro/in-Vivo Evaluation of Orally Administered Entacapone Prodrugs. J Pharm Pharmacol 2001; 53:1489–1498PubMedGoogle Scholar
  104. Leppänen J, Huuskonen J, Savolainen J, Nevalainen T, Taipale H, Vepsalainen J, Gynther J, and Jarvinen T. Synthesis of a Water-Soluble Prodrug of Entacapone. Bioorg Med Chem Lett 2000a; 10:1967–1969PubMedGoogle Scholar
  105. Leppänen JM, Huuskonen J, Savolainen J, Nevalainen T, Taipale H, Vepsalainen J, Gynther J, and Jarvinen T. Leppänen JM, Huuskonen J, Savolainen J, Nevalainen T, Taipale H, Vepsalainen J, Gynther J, and Jarvinen T. Annual AAPS Meeting, Indianapolis, IN, 2000bGoogle Scholar
  106. Li C, Yu D, Inoue T, Yang DJ, Milas L, Hunter NR, Kim EE, and Wallace S. Synthesis and Evaluation of Water-Soluble Polyethylene Glycol-Paclitaxel Conjugate as a Paclitaxel Prodrug. Anticancer Drugs 1996; 7:642–648PubMedGoogle Scholar
  107. Li C, Fleisher D, Li L, Schwier JR, Sweetana SA, Vasudevan V, Zornes LL, Pao LH, Zhou SY, and Stratford RE. Regional-Dependent Intestinal Absorption and Meal Composition Effects on Systemic Availability of LY303366, a Lipopeptide Antifungal Agent, in Dogs. J Pharm Sci 2001; 90:47–57PubMedGoogle Scholar
  108. Lin JH. Drug-Drug Interaction Mediated by Inhibition and Induction of P-Glycoprotein. Adv Drug Del Rev 2003; 55:53–81Google Scholar
  109. Lipinski CA, Lombardo F, Dominy BW, and Feeney PJ. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv Drug Deliv Rev 1997; 23:3–25Google Scholar
  110. Lipinski CA, Lombardo F, Dominy BW, and Feeney PJ. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv Drug Deliv Rev 2001; 46:3–26PubMedGoogle Scholar
  111. Lipinski CA. Poor Solubility—An Industry Wide Problem in Drug Discovery. Am Pharm Rev 2002;:82–85Google Scholar
  112. Lipinski CA. Solubility in Water and DMSO: Issues and Potential Solutions. In: Pharmaceutical Profiling in Drug Discovery for Lead Selection. AAPS Press. 2004. 93–125Google Scholar
  113. Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ, and Watkins PB. Role of Intestinal PGlycoprotein (Mdr1) in Interpatient Variation in the Oral Bioavailability of Cyclosporine. Clin Pharmacol Ther 1997; 62:248–260PubMedGoogle Scholar
  114. Maeda H, and Matsumura Y. Tumoritropic and Lymphotropic Principles of Macromolecular Drugs. Crit Rev Ther Drug Carrier Syst 1989; 6:193–210PubMedGoogle Scholar
  115. Mamber SW, Mikkilineni AB, Pack EJ, Rosser MP, Wong H, Ueda Y, and Forenza S. Tubulin Polymerization by Paclitaxel (Taxol) Phosphate Prodrugs after Metabolic Activation with Alkaline Phosphatase. J Pharmacol Exp Ther 1995; 274:877–883PubMedGoogle Scholar
  116. Mäntylä A, Garnier T, Rautio J, Nevalainen T, Vepsaelainen J, Koskinen A, Croft SL, and Jaervinen T. Synthesis, In Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone. J Med Chem 2004a; 47:188–195PubMedGoogle Scholar
  117. Mäntylä A, Rautio J, Nevalainen T, Vepsalainen J, Juvonen R, Kendrick H, Garnier T, Croft SL, and Jarvinen T. Synthesis and Antileishmanial Activity of Novel Buparvaquone Oxime Derivatives. Bioorg Med Chem 2004b; 12:3497–3502PubMedGoogle Scholar
  118. Masuda H, Ikeda M, Nagamachi M, Hirakawa Y, Yamaya H, Yoshida M, Nagayama S, and Kawaguchi Y. Metabolic Fate of TAT-59. (4th Report). Species Difference, Dose Response and Protein Binding. Yakuri to Chiryo 1998; 26:809–828Google Scholar
  119. Matsumoto H, Hamawaki T, Ota H, Kimura T, Goto T, Sano K, Hayashi Y, and Kiso Y. ‘Double-Drugs’—a New Class of Prodrug Form of an HIV Protease Inhibitor Conjugated with a Reverse Transcriptase Inhibitor by a Spontaneously Cleavable Linker. Bioorg Med Chem Lett 2000; 10:1227–1231PubMedGoogle Scholar
  120. Matsumoto H, Sohma Y, Kimura T, Hayashi Y, and Kiso Y. Controlled Drug Release: New Water-Soluble Prodrugs of an HIV Protease Inhibitor. Bioorg Med Chem Lett 2001; 11:605–509PubMedGoogle Scholar
  121. Matsunaga Y, Ohta R, Bando N, Yamada H, Yuasa H, and Kanaya Y. Effects of Water Content on Physical and Chemical Stability of Tablets Containing an Anticancer Drug TAT-59. Chem Pharm Bull 1993; 41:720–724PubMedGoogle Scholar
  122. Matsunaga Y, Bando N, Yuasa H, and Kanaya Y. Effects of Compression Pressure on Physical and Chemical Stability of Tablets Containing an Anticancer Drug TAT-59. Chem Pharm Bull 1994; 42:2582–2587PubMedGoogle Scholar
  123. Matsunaga Y, Bando N, Yuasa H, and Kanaya Y. Effects of Grinding and Tableting on Physicochemical Stability of an Anticancer Drug, TAT-59. Chem Pharm Bull 1996; 44:1931–1934PubMedGoogle Scholar
  124. McComb RB, Bowers GNJ, and Posen S. Alkaline Phosphatase. New York and London: Plenum Press. 1979Google Scholar
  125. McEvoy GK. Antineoplastic Agents:Fludarabine Phosphate. American Society of Health-System Pharmacists. 2000. p 927Google Scholar
  126. Monograph. Miproxifene Phosphate. Drugs Future 1999; 24:340–341Google Scholar
  127. Mulholland PJ, Ferry DR, Anderson D, Hussain SA, Young AM, Cook JE, Hodgkin E, Seymour LW, and Kerr DJ. Pre-Clinical and Clinical Study of Qc12, a Water-Soluble, Pro-Drug of Quercetin. Ann Oncol 2001; 12:245–248PubMedGoogle Scholar
  128. Müller RH, Jacobs C, and Kayser O. Nanosuspensions as Particulate Drug Formulations in Therapy. Rationale for Development and What We Can Expect for the Future. Adv Drug Deliv Rev 2001; 47:3–19PubMedGoogle Scholar
  129. Muther RS, and Bennett WM. Effects of Dimethyl Sulfoxide on Renal Function in Man. JAMA 1980; 244:2081–2083PubMedGoogle Scholar
  130. Neau SH. Prodrugs for Improved Aqueous Solubility. In: Liu R, editor Water-Insoluble Drug Formulation. Buffalo Grove, Ill: Interpharm Press. 2000. p 427–454Google Scholar
  131. Neuvonen PJ. Bioavailability of Phenytoin: Clinical Pharmacokinetic and Therapeutic Implications. Clin Pharmacokinet 1979; 4:91–103PubMedGoogle Scholar
  132. Niemi R, Turhanen P, Vepsalainen J, Taipale H, and Jarvinen T. Bisphosphonate Prodrugs: Synthesis and In Vitro Evaluation of Alkyl and Acyloxymethyl Esters of Etidronic Acid as Bioreversible Prodrugs of Etidronate. Eur J Pharm Sci 2000; 11:173–180PubMedGoogle Scholar
  133. NIH. 2004. Combretastatin A4 Phosphate in Treating Patients with Advanced Anaplastic Thyroid Cancer. from.: www.clinicaltrials.gov, National Institutes of HealthGoogle Scholar
  134. Nilsson T, and Jonsson G. Clinical Results with Estramustine Phosphate (NSC-89199): A Comparison of the Intravenous and Oral Preparations. Cancer Chemother Rep 1975; 59:229–232PubMedGoogle Scholar
  135. Noble S, and Goa KL. Amprenavir: A Review of Its Clinical Potential in Patients with HIV Infection. Drugs 2000; 60:1383–1410PubMedGoogle Scholar
  136. Nomura Y, Abe O, Enomoto K, Fujiwara K, Tominaga T, Hayashi K, Uchino J, Takahashi M, Hayasaka A, Asaishi K, Okazaki M, Abe R, Kimishima I, Kajiwara T, Haga S, Shimizu T, Miyazaki I, Noguchi M, Yoshida M, Miura S, Taguchi T, Oota J, Sakai K, Kinoshita H, and Tashiro H. Phase I Study of TAT-59 (a New Antiestrogen) in Breast Cancer. Gan To Kagaku Ryoho 1998a; 25:553–561PubMedGoogle Scholar
  137. Nomura Y, Nakajima M, Tominaga T, and Abe O. Late Phase II Study of TAT-59 (Miproxifene Phosphate) in Advanced or Recurrent Breast Cancer Patients (a Double-Blind Comparative Study with Tamoxifen Citrate). Gan To Kagaku Ryoho 1998b; 25:1045–1063PubMedGoogle Scholar
  138. Notari RE. Prodrug Design. Pharmacol Ther 1981; 14:25–53PubMedGoogle Scholar
  139. Novartis. Rev 7/97, Rec 2/98. Neoral and Sandimmune Package Insert. ed.: Novartis-USGoogle Scholar
  140. Noyes AA, and Whitney WR. The Rate of Solution of Solid Substances in Their Own Solutions. J Am Chem Soc 1897; 19:930–934Google Scholar
  141. Obermeier MT, Chong S, Dando SA, Marino AM, Ryono DE, Starrett-Arroyo A, DiDonato GC, Warrack BM, White RE, and Morrison RA. Prodrugs of BMS-183920: Metabolism and Permeability Considerations. J Pharm Sci 1996; 85:828–833PubMedGoogle Scholar
  142. Olivsei A. Oral Prednisolone-21-Phosphate Is Absorbed at the Same Rate and to the Same Extent as Oral Prednisolone in Normal Adults. Therapie 1985; 40:1–4Google Scholar
  143. Oliyai R, and Stella VJ. Structural Factors Affecting the Kinetics of O, N Acyl Transfer in Potential O-Peptide Prodrugs. Bioorg Med Chem Lett 1995; 5:2735Google Scholar
  144. Oscier D, Orchard JA, Culligan D, Cunningham D, Johnson S, Parker A, Klein M, and Gieschen H. The Bioavailability of Oral Fludarabine Phosphate Is Unaffected by Food. Hematol J 2001; 2:316–321PubMedGoogle Scholar
  145. Pedersen BL. Dissolution of Hydrocortisone in Human and Simulated Intestinal Fluids. Pharm Res 2000; 17:183PubMedGoogle Scholar
  146. Pendri A, Conover CD, and Greenwald RB. Antitumor Activity of Paclitaxel-2’-Glycinate Conjugated to Poly(Ethylene Glycol): A Water-Soluble Prodrug. Anticancer Drug Des 1998; 13:387–395PubMedGoogle Scholar
  147. Perry CM, and McTavish D. Estramustine Phosphate Sodium. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Prostate Cancer. Drugs Aging 1995; 7:49–74PubMedGoogle Scholar
  148. Pettit GR, Grealish MP, Jung MK, Hamel E, Pettit RK, Chapuis JC, and Schmidt JM. Antineoplastic Agents. 465. Structural Modification of Resveratrol: Sodium Resverastatin Phosphate. J Med Chem 2002; 45:2534–2542PubMedGoogle Scholar
  149. Plunkett W, Huang P, and Gandhi V. Metabolism and Action of Fludarabine Phosphate. Semin Oncol 1990; 17(5, Suppl. 8):3–17PubMedGoogle Scholar
  150. Plunkett W, Gandhi V, Huang P, Robertson LE, Yang LY, Gregoire V, Estey E, and Keating MJ. Fludarabine: Pharmacokinetics, Mechanisms of Action, and Rationales for Combination Therapies. Sem Oncol 1993; 20(5, Suppl. 7):2–12Google Scholar
  151. Polli JW, Jarrett JL, Studenberg SD, Humphreys JE, Dennis SW, Brouwer KR, and Woolley JL. Role of P-Glycoprotein on the CNS Disposition of Amprenavir (141W94), an HIV Protease Inhibitor. Pharm Res 1999; 16:1206–1212PubMedGoogle Scholar
  152. Ramis J, Torrent J, Mis R, Barbanoj M, Abadias M, Jane F, and Forn J. Pharmacokinetics of Fosfosal after Single and Multiple Oral Doses in Man. Int J Clin Pharmacol Ther Toxicol 1988; 26:421–427PubMedGoogle Scholar
  153. Rao VM, and Stella VJ. When Can Cyclodextrins Be Considered for Solubilization Purposes? J Pharm Sci 2003; 92:927–932PubMedGoogle Scholar
  154. Reid RC, and Prausnitz JM. The Properties of Gases and Liquids. New York: McGraw-Hill. 1977. pp 57–59, 573Google Scholar
  155. Rigalli A, Cabrerizo MA, Beinlich AD, and Puche RC. Gastric and Intestinal Absorption of Monofluorophosphate and Fluoride in the Rat. Arzneimittelforschung 1994; 44:651–655PubMedGoogle Scholar
  156. Rodriguez MJ, Vasudevan V, Jamison JA, Borromeo PS, and Turner WW. The Synthesis of Water Soluble Prodrugs Analogs of Echinocandin B. Bioorg Med Chem Lett 1999; 9:1863–1868PubMedGoogle Scholar
  157. Rossi JF, van Hoof A, de Boeck K, Johnson SA, Bron D, Foussard C, Lister TA, Berthou C, Kramer MHH, Littlewood TJ, Marcus RE, Deconinck E, Montillo M, Guibon O, and Tollerfield SM. Efficacy and Safety of Oral Fludarabine Phosphate in Previously Untreated Patients with Chronic Lymphocytic Leukemia. J Clin Oncol 2004; 22:1260–1267PubMedGoogle Scholar
  158. Rothbard JB, Garlington S, Lin Q, Kirschberg T, Kreider E, McGrane PL, Wender PA, and Khavari PA. Conjugation of Arginine Oligomers to Cyclosporin A Facilitates Topical Delivery and Inhibition of Inflammation. Nat Med 2000; 6:1253–1257PubMedGoogle Scholar
  159. Rouquayrol M, Gaucher B, Roche D, Greiner J, and Vierling P. Transepithelial Transport of Prodrugs of the HIV Protease Inhibitors Saquinavir, Indinavir, and Nelfinavir across Caco-2 Cell Monolayers. Pharm Res 2002; 19:1704–1712PubMedGoogle Scholar
  160. Ruggeri B, Yang S, Pritchard S, Singh J, Gingrich DE, Angeles T, Albom M, Chang H, Robinson C, Hunter K, Dobrzanski P, Jones-Bolin S, Aimone L, Klein-Szanto A, Herbert JM, Bono F, Schaeffer P, Casellas P, Bourie B, Pili R, Isaacs J, Ator M, Hudkins R, Vaught J, Mallamo J, and Dionne C. CEP-7055: A Novel, Orally Active Pan Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models. Cancer Res 2003; 63:7543Google Scholar
  161. Ruiz-Balaguer N, Nacher A, Casabo VG, and Merino M. Nonlinear Intestinal Absorption Kinetics of Cefuroxime Axetil in Rats. Antimicrob Agents Chemother 1997; 41:445–448PubMedGoogle Scholar
  162. Santos NC, Figueira-Coelho J, Martins-Silva J, and Saldanha C. Multidisciplinary Utilization of Dimethyl Sulfoxide: Pharmacological, Cellular, and Molecular Aspects. Biochem Pharmacol 2003; 65:1035–1041PubMedGoogle Scholar
  163. Savolainen J, Leppänen J, Forsberg M, Taipale H, Nevalainen T, Huuskonen J, Gynther J, Mannisto PT, and Jarvinen T. Synthesis and In Vitro/In Vivo Evaluation of Novel Oral N-Alkyl-and N,N-Dialkyl-Carbamate Esters of Entacapone. Life Sci 2000a; 67:205–216PubMedGoogle Scholar
  164. Savolainen J, Forsberg M, Taipale H, Mannisto PT, Jarvinen K, Gynther J, Jarho P, and Jarvinen T. Effects of Aqueous Solubility and Dissolution Characteristics on Oral Bioavailability of Entacapone. Drug Dev Res 2000b; 49:238–244Google Scholar
  165. Schacter L. Etoposide Phosphate: What, Why, Where, and How? Semin Oncol 1996;23(6 Suppl 13):1–7PubMedGoogle Scholar
  166. Selen A. Factors Influencing Bioavailability and Bioequivalence. In: Welling PG, Tse FLS, and Dighe SV, editors. Pharmaceutical Bioequivalence. New York Basel Hong Kong: Marcel Dekker, Inc. 1991Google Scholar
  167. Shah JC, Chen JR, and Chow D. Preformulation Study of Etoposide: Identification of Physicochemical Characteristics Responsible for the Low and Erratic Oral Bioavailability of Etoposide. Pharm Res 1989; 6:408–412PubMedGoogle Scholar
  168. Shen TT, and Winter CA. Chemical and Biological Studies on Indomethacin, Sulindac and Their Analogs. In: Harper NJ, and Simmonds AB, editors. Advances in Drug Research. London, England: Academic Press. 1977. p 89–245Google Scholar
  169. Shore PA, Brodie BB, Adrian C, and Hogben M. The Gastric Secretion of Drugs: A pH Partition Hypothesis. J Pharmacol Exp Ther 1957; 119:361–369PubMedGoogle Scholar
  170. Sietsema WK. The Absolute Oral Bioavailability of Selected Drugs. Int J Clin Pharmacol Ther Toxicol 1989; 27:179–211PubMedGoogle Scholar
  171. Sinko PJ, and 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; 19:209–217PubMedGoogle Scholar
  172. Skwarczynski M, Sohma Y, Kimura M, Hayashi Y, Kimura T, and Kiso Y. O-N Intramolecular Acyl Migration Strategy in Water-Soluble Prodrugs of Taxoids. Bioorg Med Chem Lett 2003; 13:4441–4444PubMedGoogle Scholar
  173. Smiley ML, Murray A, and De Miranda Pd. Valacyclovir HCl (Valtrex): An Acyclovir Prodrug with Improved Pharmacokinetics and Better Efficacy for Treatment of Zoster. Adv Exp Med Biol 1996; 394:33–39PubMedGoogle Scholar
  174. Sobue S, Tan K, Layton G, Eve M, and Sanderson JB. Pharmacokinetics of Fosfluconazole and Fluconazole Following Multiple Intravenous Administration of Fosfluconazole in Healthy Male Volunteers. Br J Clin Pharmacol 2004; 58:20–25PubMedGoogle Scholar
  175. Soejima R, and Saito A. Reevaluation of Current Antimicrobials. Clindamycin Phosphate. Jpn J Antibiot 1994; 47:845–852PubMedGoogle Scholar
  176. Sohma Y, Hayashi Y, Ito T, Matsumoto H, Kimura T, and Kiso Y. Development of Water-Soluble Prodrugs of the HIV-1 Protease Inhibitor KNI-727: Importance of the Conversion Time for Higher Gastrointestinal Absorption of Prodrugs Based on Spontaneous Chemical Cleavage. J Med Chem 2003; 46:4124–4135PubMedGoogle Scholar
  177. Soltau J, and Drevs J. Zd-6126 (Astra Zeneca). Drugs 2004; 7:380–387Google Scholar
  178. Sorbera LA, Martin L, Castaner J, and Castaner RM. Fosamprenavir. Drugs Fut 2001; 26:224–231Google Scholar
  179. Stahl PH. Preparation of Water-Soluble Compounds through Salt Formation. Practice of Medicinal Chemistry (2nd Edition) 2003:601–615Google Scholar
  180. Stella VJ. A Case for Prodrugs: Fosphenytoin. Adv Drug Del Rev 1996; 19:311–330Google Scholar
  181. Stella VJ. Prodrugs as Therapeutics. Expert Opin Ther Patents 2004; 14:277–280Google Scholar
  182. Stella VJ, Charman WN, and Naringrekar VH. Prodrugs. Do They Have Advantages in Clinical Practice? Drugs 1985; 29:455–473PubMedGoogle Scholar
  183. Stella VJ, Martodihardjo S, Terada K, and Rao VM. Some Relationships between the Physical Properties of Various 3-Acyloxymethyl Prodrugs of Phenytoin to Structure: Potential In Vivo Performance Implications. J Pharm Sci 1998; 87:1235–1241PubMedGoogle Scholar
  184. Stewart BH. Improving the Intestinal Absorption of Water-Insoluble Compounds and the Specificity of Targeted Drug Delivery. Ph.D. Thesis. Ann Arbor, MI: The University of Michigan. 1986Google Scholar
  185. Strickley RG. Solubilizing Excipients in Oral and Injectable Formulations. Pharm Res 2004; 21:201–230PubMedGoogle Scholar
  186. Sun D, Yu LX, Hussain MA, Wall DA, Smith RL, and Amidon GL. 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; 7:75–85PubMedGoogle Scholar
  187. Tamamura H, Ishihara T, Oyake H, Imai M, Otaka A, Ibuka T, Arakaki R, Nakashima H, Murakami T, Waki M, Matsumoto A, Yamamoto N, and Fujii N. Convenient One-Pot Synthesis of Cystine-Containing Peptides Using the Trimethylsilyl Chloride-Dimethyl Sulfoxide/Trifluoroacetic Acid System and Its Application to the Synthesis of Bifunctional Anti-HIV Compounds. J Chem Soc Perkin Trans 1998; 1:495–500Google Scholar
  188. Taniguchi M, and Nakano M. Study of Phosphate Esters as Prodrugs. Part 3. Synthesis and Evaluation In Vitro of 4-Acetamidophenyl Phosphate. Chem Pharm Bull 1981; 29:577–580Google Scholar
  189. Terwogt JMM, Malingre MM, Beijnen JH, Huinink WWtB, Rosing H, Koopman FJ, Van Tellingen O, Swart M, and Schellens JH. Coadministration of Oral Cyclosporin A Enables Oral Therapy with Paclitaxel. Clin Cancer Res 1999; 5:3379–3384Google Scholar
  190. Testa B, and Mayer JM. Concepts in Prodrug Design to Overcome Pharmacokinetic Problems. Zürich: Verlag Helvetica Chimica Acta. 2001Google Scholar
  191. Toko T, Sugimoto Y, Matsuo K, Yamasaki R, Takeda S, Wierzba K, Asao T, and Yamada Y. TAT-59, a New Triphenylethylene Derivative with Antitumor Activity against Hormone-Dependent Tumors. Eur J Cancer 1990; 26:397–404PubMedCrossRefGoogle Scholar
  192. Tong WQ. Preformulation Aspects of Insoluble Compounds. In: Liu R, editor Water-Insoluble Drug Formulation. Way East Englewood, CO: Interpharm Press. 2000. p 65–95Google Scholar
  193. Tritsch GL, Shukla SK, Mittelman A, and Murphy GP. Estracyt (NSC 89199) as a Substrate for Phosphatases in Human Serum. Invest Urol 1974; 12:38–39PubMedGoogle Scholar
  194. Ueda Y, Mikkilineni AB, Knipe JO, Rose WC, Casazza AM, and Vyas DM. Novel Water Soluble Phosphate Prodrugs of Taxol Possessing In Vivo Antitumor Activity. Bioorg Med Chem Lett 1993; 3:1761–1766Google Scholar
  195. van Asten P, Duursma SA, Glerum JH, Ververs FF, van Rijn HJ, and van Dijk A. Absolute Bioavailability of Fluoride from Disodium Monofluorophosphate and Enteric-Coated Sodium Fluoride Tablets. Eur J Clin Pharmacol 1996; 50:321–326PubMedGoogle Scholar
  196. Van Gelder J, Deferme S, Annaert P, Naesens L, De Clercq E, Van den Mooter G, Kinget R, and Augustijns P. Increased Absorption of the Antiviral Ester Prodrug Tenofovir Disoproxil in Rat Ileum by Inhibiting Its Intestinal Metabolism. Drug Metabol Dispos 2000; 28:1394–1396Google Scholar
  197. Varia SA, and Stella VJ. Phenytoin Prodrugs V: In Vivo Evaluation of Some Water-Soluble Phenytoin Prodrugs in Dogs. J Pharm Sci 1984; 73:1080–1087PubMedGoogle Scholar
  198. Wadsten T, and Lindberg NO. Polymorphism of Estramustine. J Pharm Sci 1989; 78:563–566PubMedGoogle Scholar
  199. Wakamiya T, Tarumi Y, and Shiba T. Inversion of Configuration of Threonine and Allothreonine in N,O-Acyl Migration Reaction with Concentrated Sulfuric Acid. Bull Chem Soc Jp 1974; 47:2686–2689Google Scholar
  200. Walsh P. Physicians’ Desk Reference. Medical Economics Company, Inc. 2000. pp. 1805Google Scholar
  201. Ward KW, Proksch JW, Levy MA, and Smith BR. Development of an In Vivo Preclinical Screen Model to Estimate Absorption and Bioavailability of Xenobiotics. Drug Metabol Dispos 2001; 29:82–88Google Scholar
  202. Wermuth CG. Drug Design: Fact or Fantasy? London: Academic Press. 1984. p 47–72Google Scholar
  203. Winne D. Shift of pH-Absorption Curves. J Pharmacokinet Biopharm 1977; 5:53–94PubMedGoogle Scholar
  204. Wipf P, Li W, and Sekhar V. Synthesis of Chemoreversible Prodrugs of Ara-C. Bioorg Med Chem Lett 1991; 1:745–750Google Scholar
  205. Wipf P, Li W, Adeyeye CM, Rusnak JM, and Lazo JS. Synthesis of Chemoreversible Prodrugs of Ara-C with Variable Time-Release Profiles. Biological Evaluation of Their Apoptotic Activity. Bioorg Med Chem 1996; 4:1585–1596PubMedGoogle Scholar
  206. Wood R, Arasteh K, Stellbrink H-J, Teofilo E, Raffi F, Pollard Richard B, Eron J, Yeo J, Millard J, Wire Mary B, and Naderer Odin J. Six-Week Randomized Controlled Trial to Compare the Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients. Antimicrob Agents Chemother 2004; 48:116–123PubMedGoogle Scholar
  207. Yagi S, Ono J, Yoshimoto J, Sugita K-I, Hattori N, Fujioka T, Fujiwara T, Sugimoto H, Hirano K, and Hashimoto N. Development of Anti-Influenza Virus Drugs I: Improvement of Oral Absorption and In Vivo Anti-Influenza Activity of Stachyflin and Its Derivatives. Pharm Res 1999; 16:1041–1046PubMedGoogle Scholar
  208. Yoshimoto J, Yagi S, Ono J, Sugita K, Hattori N, Fujioka T, Fujiwara T, Sugimoto H, and Hashimoti N. Development of Anti-Influenza Drugs: II. Improvement of Oral and Intranasal Absorption and the Anti-Influenza Activity of Stachyflin Derivatives. J PharmPharmacol 2000; 52:1247–1255Google Scholar
  209. Young SL, and Chaplin DJ. Combretastatin A4 Phosphate: Background and Current Clinical Status. Expert Opin Investig Drugs 2004; 13:1171–1182PubMedGoogle Scholar
  210. Yu LX. An Integrated Model for Determining Causes of Poor Oral Drug Absorption. Pharm Res 1999; 16:1883–1887PubMedGoogle Scholar
  211. Yuasa H, Matsuda K, Gu J, Suzuki E, Yokouchi I, and Watanabe J. Dose-Dependent Gastrointestinal Absorption of 5-Fluorouracil in Rats In Vivo. Biol. Pharm Bull 1996; 19:1494–1498PubMedGoogle Scholar
  212. Zhang H, and Yu L. Dissolution Testing for Solid Oral Drug Products: Theoretical Considerations. Am Pharm Rev 2004; 7:26–30Google Scholar
  213. Zhu Z, Chen H-G, Goel OP, Chan OH, Stilgenbauer LA, and Stewart BH. Phosphate Prodrugs of PD 154075. Bioorg Med Chem Lett 2000; 10:1121–1124PubMedGoogle Scholar
  214. Zornes LL, Stratford RE, Novilla M, Turner D, and Boylan C. Single Dose IV Bolus and Oral Administration of LY303366, a Lipopeptide Antifungal Agent Related to Echinochandin B, in female Lewis Rats and Beagle Dogs 33rd ICAAC, New Orleans, LA, 1993, Abstract 370.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Tycho Heimbach
    • 1
  • David Fleisher
    • 2
  • Amal Kaddoumi
    • 2
  1. 1.Department of Pharmacokinetics, Dynamics, and MetabolismPfizer Global Research and DevelopmentAnn Arbor
  2. 2.College of PharmacyThe University of MichiganAnn Arbor

Personalised recommendations