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Prodrugs for the improvement of drug absorption via different routes of administration

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Summary

The authors critically review recent knowledge on the use of prodrugs to improve drug absorption. Main emphasis is placed on the parenteral, oral, transdermal and ocular routes. Mechanisms for drug absorption enhancement and bioavailability assessment are discussed. Some other applications of prodrugs are also examined. Finally, some comments are made regarding the present situation and future trends in prodrug design and their implications in biopharmaceutics and pharmacokinetics.

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References

  1. Albert A. (1958): Chemical aspects of selective toxicity. Nature, 182, 421–423.

    Article  PubMed  CAS  Google Scholar 

  2. Higuchi T., Stella V. (1975): Pro-drugs as Novel Drug Delivery Systems. Am. Chem. Soc. Washington DC.

    Book  Google Scholar 

  3. Roche E.B. (1977): Design of Biopharmaceutical Properties through Prodrugs and Analogs. American Pharmaceutical Association / Academy of Pharmaceutical Sciences Symposium Washington D.C.

  4. Higuchi W.I., Kusai A., Fox J.L., Gordon N.A., Ho N.F.H, Hsu C.C., Baker D.C., Shannon W.M. (1983): Controlled release of drugs: Prodrug performance in target tissues. In: Controlled Release Delivery Systems, T.J. Roseman & S.Z. Mansdorf. eds Marcel Dekker, New York, pp. 43–76.

    Google Scholar 

  5. Waller D.G., George C.F. (1989): Prodrugs. Brit. J. Clin. Pharmacol. 28, 497–507.

    CAS  Google Scholar 

  6. Sinkula A.A. (1977): Design of Biopharmaceutical Properties through Prodrugs and Analogs. Roche EB ed. Am. Pharm. Assoc. & Acad Pharm. Sci., Washington DC, pp. 1–17.

    Google Scholar 

  7. Balant-Gorgia A.E., Balant L.P. (1987): Antipsychotic drugs. Clinical pharmacokinetics of potential candidates for plasma concentration monitoring. Clin. Pharmacolcin. 13, 65–90.

    Article  CAS  Google Scholar 

  8. Bundgaard H. Nielsen N.M. (1988): Gh/colamide esters as a novel biolabile prodrug type for non — steroidal anti-inflammatory carboxylic acid drugs. Int. J. Pharm., 43, 101–110.

    Article  CAS  Google Scholar 

  9. Bundgaard H., Nielsen N.M., Buur A. (1988a): Aspirin prodrugs: synthesis and hydrolysis of 2 — acetoxybentzoate esters of various N — (hydroxyalkyi) amides. Int. J. Pharma, 44, 151–158.

    Article  CAS  Google Scholar 

  10. Biasio R.B., Harris B.E. (1989): Clinical pharmacology of 5 — fluorouracil. Clin. Pharmacokin., 16, 215–237.

    Article  Google Scholar 

  11. Buur A., Bundgaard H. (1986): Prodrugs of 5-fluorouracil. V. 1-Alkoxycarbony) derivatives as potential prodrug forms for improved rectal or oral delivery of 5-fluorouracil. J. Pharm. Sci., 75, 522–527.

    Article  PubMed  CAS  Google Scholar 

  12. Buur A., Bundgaard H. (1987): Prodrugs of 5-fluorouracil. VIII. Improved rectal and oral delivery of 5-fluorouracil via various prodrugs. Structure — rectal absorption relationships. Int. J. Pharm., 36, 4149.

    Article  Google Scholar 

  13. Schaaf L.J., Dobbs B.R., Edwards I.R., Perrier D.G. (1988): The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer. Eur. J. Clin. Pharmacol., 34, 439–443.

    Article  PubMed  CAS  Google Scholar 

  14. Pardridge W.M. (1983): Brain metabolism: a perspective from the blood — brain barrier. Physiol. Rev., 63, 1481–1535.

    PubMed  CAS  Google Scholar 

  15. Dayer P., Desmeules J., Leemann T., Striberni R. (1988): Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation. Biochem. Biophys. Res. Commun., 152, 411–416.

    Article  PubMed  CAS  Google Scholar 

  16. Desmeules J., Dayer P., Gascon M.P., Magistris M. (1989): Impact of genetic and environmental factors on codeine analgesia. Clin. Pharmacol., 45, 122.

    Google Scholar 

  17. Inturrisi C.E., Mitchell B.M., Foley K.M., Schulz M., Seung-Uon S., Houde R.W., (1984): The pharmacokinetics of heroin in patients with chronic pain. New Engl. J. Med., 310, 1213–1217.

    Article  PubMed  Google Scholar 

  18. Duggan D.E., Hare L.E., Ditzler C.A., Lei B.W., Kwan K.C. (1977): The disposition of sulindac in man. Clin. Pharmacol. ther., 21, 326–335.

    PubMed  CAS  Google Scholar 

  19. Duggan D.E., Hooke K.F., Noll R.M., Hucker H.B. Van Arman C.G. (1978): Comparative disposition of sulindac and metabolites in five species. Biochem. Pharmacol., 27, 2311–2320.

    Article  PubMed  CAS  Google Scholar 

  20. Tatsumi K., Kitimura S., Yanada S. (1983): Sulfoxide reductase activity of liver aldehyde oxidase. Biochem. Biophys. Acta, 747, 86–92

    PubMed  CAS  Google Scholar 

  21. Strong H.A., Warner N.J., Renwick A.G., George C.F. (1985): Sutindac metabolism: The importance of an intact colon. Clin. Pharmacol. Ther., 38, 387–393.

    Article  PubMed  CAS  Google Scholar 

  22. Colvin M., Brundrett R.B., Kan M.N.N., Jardine I., Feneslau C. (1976): Alkylating properties of phosphoramide mustard. Cancer Res., 36, 1121–1126.

    PubMed  CAS  Google Scholar 

  23. Sinkula A.A., Yalkowsky S.H. (1975): Rationale for design of biologically reversible drug derivatives: Prodrugs. J. Pharm. Sci., 64, 181–210.

    Article  PubMed  CAS  Google Scholar 

  24. Aguiar A., Zelmer J.E. (1969): Dissolution behavior of polymorphs of chloramphenicol palmitate and mefenamic acid. J. Pharm. Sci., 58, 983–987.

    Article  PubMed  CAS  Google Scholar 

  25. Burger A. (1977): Neue Untersuchungergebnisse von Chloramphenicolpalmitat. Sci. Pharm., 45, 269–281.

    CAS  Google Scholar 

  26. Olsson C.A., Svensson L.A. (1984): New lipophilic terbutaline ester prodrugs with long effect duration. Pharm. Res., 1, 19–23.

    Article  Google Scholar 

  27. Sloan K.B., Bodor N. (1982): Hydroxymethyl and aeycloxymethyl prodrugs of theophylline: Enhanced delivery of polar drugs through skin. Int. J. Pharm., 12, 299–313.

    Article  CAS  Google Scholar 

  28. Johansen M., Bundgaard H. (1981): Decomposition of rotitetracycline and other N-Mannich bases and of N-hydroxymethyl derivatives in the presence of plasma. Arch. Pharm. Chem. Sci., 9, 40–42.

    CAS  Google Scholar 

  29. Vert M. (1986): Polyvalent polymeric drug carriers. Critical Reviews in Theapeutic Drug Carrier Systems, 2, CRC Press, Boca Raton, FL, pp. 291–327.

    Google Scholar 

  30. Ringsdorf H. (1975): Structure and properties of pharmacologically active polymers. J. Polym. Sci. Polym. Symp, 51, 135–153.

    Article  CAS  Google Scholar 

  31. Larsen C. (1989): Macromolecular prodrug. XII. Kinetics of release of naproxen from various polysaccharide ester prodrugs in neutral and alkaline solution. Int. J. Pharm., 51, 223–240.

    Google Scholar 

  32. Kratzl K., Kaufmann E. (1961): Versuche zur Darstellung hochmolekularer Pharmazeutika. 1. Mitt.: Synthese, Reaktionen und C-Markierung eines Acetylsalicylsaurestarkeesters. Monatschr. Chem., 92, 371–378.

    CAS  Google Scholar 

  33. Kratzl K., Kaufmann E., Kraupp O., Stormann H. (1961): Versuche zur Darstellung hochmolekularer Pharmazeutika. 2. Mitt.: Stoffwechscluntersuchungen von Aeetylsalicylsaurestarkeestern. Monatschr. Chem., 92, 378–383.

    Google Scholar 

  34. Schacht E., Ruys E., Vermeesrch J., Renion J.P. (1984): Polymer — drug combinations: Synthesis and characterization of modified polysaccharides containing procainamide moieties. J. Control. Rel., 1, 33–46.

    Article  CAS  Google Scholar 

  35. Remon J.P., Duncan R., Schacht E. (1984): Polymer-drug combinations: Pinocytic uptake of modified polysaccharides containing procainamide moieties by rat visceral yolk sacs cultured in vitro. J. Control. Rel., 1, 47–56.

    Article  CAS  Google Scholar 

  36. Kojima T., Hashida M., Muranishi S., Sezaki H. (1978): Antitumor activity of timed — release derivative of mitomycin C, agarose bead conjugate. Chem. Pharm. Bull, 26, 1818–1824.

    PubMed  CAS  Google Scholar 

  37. Tritton T.R., Yee G., Wingaard L.B. (1983): Immobilized adriamycin: A tool for separating cell surface from intracellular mechanisms. Fed. Proc., 42, 284–287.

    PubMed  CAS  Google Scholar 

  38. Puglisi L., Caruso V., Paoletti R., Ferruti P., Tanzi M.C. (1976): Macromolecular drugs. I: Long — lasting antilipolytic activity of nicotinic acid bound to a polymer. Pharmacol. Res. Commun. 8, 379–386.

    Article  PubMed  CAS  Google Scholar 

  39. Havron A., Weiner B.Z., Zilkha A., (1974): Polymeric salicylate derivatives. J. Med. Chem., 17, 770–772.

    Article  PubMed  CAS  Google Scholar 

  40. McCormick C.L., Lichatowich D.K. (1979): Homogenous solution reactions of cellulose, chitin and other polysaccharides to produce controlled — activity pesticide systems. J. Polym, Sci., Polym. Ed., 17, 479–484.

    CAS  Google Scholar 

  41. Singh M., Vasudevan P., Sinha T.J.M., Ray A.R., Misro M.M., Guha K. (1981): An insulin delivery system from oxidized cellulose. J. Biomed. Mater. Res., 15, 655–661.

    Article  PubMed  Google Scholar 

  42. Yolles S., Morton J.F., Sartori M.F. (1979): Preparation of steroid esters of hydroxypropyl cellulose. J. Polym. Sci. Polym. Chem. Ed., 17, 4111–4113.

    Article  CAS  Google Scholar 

  43. Yolles S. (1987): Time — release depot for anticancer drugs: Release of drugs covalently bound to polymers. J. Parenter. Drug Assoc., 32, 188–191.

    Google Scholar 

  44. Rohdewald P., Mollmann H., Barth J., Rehder J., Derendoig H. (1987): Pharmacokinetics of dexamethazone and its phosphate ester. Biopharm. Drug Dispos., 8, 205–212.

    Article  PubMed  CAS  Google Scholar 

  45. Sendo F., Riley C., Stella V.J., (1988): Kinetics of hydrolysis of fetindomide (NSD-373965), bis-N, N′-phenylalanyloxymethyl prodrug of mitindomide (NSC-284356); an unexpected catalytic effect of generated formaldehyde. Int. J. Pharm., 45, 207–216.

    Article  CAS  Google Scholar 

  46. Nahata M.C., Powell D.A. (1981): Bioavailability and clearance of chloramphenicol after intravenous chloramphenicol succinate. Clin. Pharmacol., Ther. 30, 368–372.

    Article  CAS  Google Scholar 

  47. Burke J., Wargin W.A., Sherertz R.J., Sanders K.L., Blum M.R., Sarubbi F.A. (1982): Pharmacokinetics of intravenous chloramphenicol sodium succinate in adult patients with normal renal and hepatic function. J. Pharmacokin. BioPharm., 6, 601–614.

    Article  Google Scholar 

  48. Schwartz M.A., Hayton W.L. (1972): Relative stability of hetacillin and ampieillin in solution. J. Pharm. Sci., 61, 906–909.

    Article  PubMed  CAS  Google Scholar 

  49. Nguygen N.A., Mortada L.M., Notari R.E. (1988): Potential improvement in the shelf life of parenterals using the prodrug approach: Bacampicillin and talampicillin hydrolysis kinetics and utilization time. Pharm. Res., 5, 288–296.

    Article  Google Scholar 

  50. Nyuyen N.A., Notari R.E. (1988): Potential improvement in shelf life using the prodrug approach. II. A systematic examination of kinetic requirements. Pharm. Res., 5, 634–638.

    Article  Google Scholar 

  51. Leight D.A., Reeves D.S., Simmons K., Thomas A.L., Wilkinson P.J. (1976): Talampicillin a new derivative of ampieillin Brit. Med. J., 1, 1378–1380.

    Article  Google Scholar 

  52. Ehrnebo M., Nilsson S.O., Boreus L.O. (1979): Pharmacokinetics of ampieillin and its prodrugs bacampicillin and pivampicillin in man. J. Pharmacokin. BioPharm., 7, 429–451.

    Article  CAS  Google Scholar 

  53. Rozencweig M., Staquet M., Klastersky J. (1976): Antibac terial activity and pharmacokinetics of bacampicillin and ampicillin. Clin. Pharmacol. Ther., 19, 592–597.

    PubMed  CAS  Google Scholar 

  54. Yoshimura Y., Hamaguchi N., Yashiki T. (1987): Synthesis and oral absorption of acyloxymethyl esters of cefotiam. Int. J. Pharm., 38, 179–190.

    Article  CAS  Google Scholar 

  55. Vickers S., Duncan C.A., White S.D., Breault G.O., Royds R.B., DeSchepper P.J. Tempero K.F. (1978): Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog and rat. Drug Metab. Dispos., 6, 646–649.

    Google Scholar 

  56. Vickers S., Duncan C.A.H., Ramjit H.G., Dobrinska M.R., Dollery C., Gomez H.J., Leidy H.L., Vincek W.C. (1984): Metabolism of methyldopa in man after oral administration of the pivaloxyloxyethyl ester. Drug Metab. Dispos., 12, 242–246.

    PubMed  CAS  Google Scholar 

  57. Dobrinska M.R., Kukovetz W., Beubler E., Leidy H.L., Gomez H.J., Demetgriades J., Bolognese J.A. (1982): Pharmacokinetics of the pivaloyloxyethyl (POE) ester of methyldopa, a new prodrug of methyldopa. H. Pharmacokin. BioPharm., 10, 587–600.

    Article  CAS  Google Scholar 

  58. Wagner J., Grill H., Henschler D. (1980): Prodrugs of etilefrine: Synthesis and evaluation of 3′-(O-acyl) derivatives. J. Pharm. Sci., 69, 1423–1427.

    Article  PubMed  CAS  Google Scholar 

  59. Bodor N., Sloan K.B., Higuchi T., Sasahara K. (1977): Improved delivery through biological membranes. 4. Prodrugs of L-Dopa. J. Med. Chem., 20, 1435–1445.

    Article  PubMed  CAS  Google Scholar 

  60. Hornblad Y., Ripe E., Magnusson P.O., Tegnes K. (1976): The metabolism and clinical activity of terbutaline and its prodrug ibuterol. Eur. J. Clin. Pharmacol., 10, 9–18.

    Article  Google Scholar 

  61. D’ Souza M., Vankataraman R., D’ Mello A., Niphadkar P., (1986): An alternative prodrug approach for reducing presystemic metabolism of drugs. Int. J. Pharm., 31, 165–167.

    Article  Google Scholar 

  62. Sasaki H., Takahashi T., Nakamura J., Konishi J., Shibasaki J. (1986): Intestinal absorption of 5-fluorouracil and its alkylcarbamoyl derivatives in the rat small intestine. J. Pharm. Sci., 75, 676–679.

    Article  PubMed  CAS  Google Scholar 

  63. Basu K., Kildsig D.O., Mitra A.K. (1988): Synthesis and kinetic stability studies of progesterone derivatives. Int. J. Pharm., 47, 195–203.

    Article  CAS  Google Scholar 

  64. Hussain M.A., Koval C.A., Myers M.J., Shami E.G., Shefter E. (1987): Improvement of the oral bioavailability of naltrexone in dogs: A prodrug approach. J. Pharm. Sci., 76, 356–358.

    Article  PubMed  CAS  Google Scholar 

  65. Hussain M.A., Shefter E. (1988): Naltrexone -3- salicylate (a prodrug of naltrexone): Synthesis and pharmacokinetics in dogs. Pharm. Res., 5, 113–115.

    Article  PubMed  CAS  Google Scholar 

  66. Buur A., Bundgaard H. (1988): Prodrugs of peptides. III. 5-Oxazolidinones as bioreversible derivatives for the a-amido carboxy moiety in peptides. Int. J. Pharm., 46, 159–167.

    Article  CAS  Google Scholar 

  67. Anderson B.D., Chu W.W., Galinsky R.E. (1988): Reduction of first — pass metabolism of propranolol after oral administation of esters prodrugs. Int. J. Pharm., 43, 261–265.

    Article  CAS  Google Scholar 

  68. Aungst B.J., Myers M.J., Shefter E., Shami E.G. (1987): Prodrugs for improved oral nalbuphine bioavailability: Interspecies differences in the disposition of nalbuphine and its acetysalicylate and anthranilate esters. Int. J. Pharm., 38, 199–209.

    Article  CAS  Google Scholar 

  69. Saab A.N., Ditter L.W., Hussain A.A. (1988): Isomerization of cephalosporin esters: Implications for the prodrug ester approach to enhancing the oral bioavailability of cephalosporins. J. Pharm. Sci., 77, 906–907.

    Article  PubMed  CAS  Google Scholar 

  70. Negishi N., Bennett D.B., Cho C.S., Jeong S.Y. Van Heeswijk W.A.R., Feijen J., Kin S.W. (1987): Coupling of natrexone to biodegradable poly (a-amino acids). Pharm. Res., 4, 305–310.

    Article  PubMed  CAS  Google Scholar 

  71. Mesland J.C., Vean L., Subira F., Vairon J.P. (1986): Reversible immobilization of drugs on a hydrogen matrix. Makromol. Chem., 187, 787–794.

    Article  Google Scholar 

  72. Chafi N., Momheard J.P., Vergnaud J.M. (1988): Dosage form with drug attached to polymer (poh/anhydride) dispersed in a Eudriagit matrix: Preparation and release of drug in gastric liquid. Int. J. Pharm., 45, 229–236.

    Article  CAS  Google Scholar 

  73. Irwin W.J., Belaid K.A. (1988a): Drug-delivery by ion-exchange. Hydrolysis and rearrangement of ester pro-drugs of propranolol. Int. J. Pharm., 46, 57–67.

    Article  CAS  Google Scholar 

  74. Irwin W.J., Belaid K.A. (1988b): Drug-delivery by ion-exchange. Stability of ester prodrugs of propranolol in surfactant and enzymatic systems. Int. J. Pharm., 48, 159–166.

    Article  CAS  Google Scholar 

  75. Kaneo Y., Tanaka T., Fujihara Y., Mori H., Iguchi S. (1988): Delivery of glutathione, as a dextran conjugate, into the liver. Int. J. Pharm., 44, 265–267.

    Article  CAS  Google Scholar 

  76. Chan S.Y., Li Van Po A. (1989): Prodrugs for dermal delivery. Int. J. Pharm. 55, 1–16.

    Article  CAS  Google Scholar 

  77. Yu C.D., Fox J.L., Ho N.F.H., Higuchi W.I. (1979): Physical model evalution of topical prodrug delivery — Simultaneous transport and bioconversion of vidarabine-5’-valerate. I. Physical model development. J. Pharm. Sci., 68, 1341–1346.

    Article  PubMed  CAS  Google Scholar 

  78. Loftosson T., Bodor N. (1981): Improved delivery through biological membranes IX-X. J. Pharm. Sci., 70, 750–758.

    Article  Google Scholar 

  79. Sloan K.B., Koch S.A.M., Silver K.G. (1984a): Mannich base derivatives of theophylline and 5-fluorouracil: Syntheses, properties and topical delivery characteristics. Int. J. Pharm., 21, 251–254.

    Article  CAS  Google Scholar 

  80. Sloan K.B., Sherertz E.F., McTiernan R.G. (1988): The effect of structure of Mannich base prodrugs on their ability to deliver theophylline and 5-fluoro uracil trough hairless mouse skin. Int. J. Pharm., 44, 87–96.

    Article  CAS  Google Scholar 

  81. Sloan K.B., Hashida M., Alexander J., Bodor B., Higuchi T. (1983): Prodrugs of 6-thiopurines. Enhanced delivery trough the skin. J. Pharm. Sci., 72, 372–378.

    Article  PubMed  CAS  Google Scholar 

  82. Siver K.G., Sloan K.B. (1988): The effect of structure of Mannich base prodrugs of 6-mercaptopurine on their ability to deliver 6-mercaptopurine trough hairless mouse skin. Int. J. Pharm., 48, 195–206.

    Article  CAS  Google Scholar 

  83. Mollgaard B., Hoelgaard A., Bundgaard H. (1982): Pro-drugs as drug delivery systems. XXIII. Improved dermal delivery of 5-fluorouracil through human skin via N-acyloxymethyl prodrug derivatives. Int. J. Pharm., 12, 153–162.

    Article  Google Scholar 

  84. Sloan K.B., Selk S., Haslam J. Caldwell L., Shaffer R. (1984b): Acyloxyamines as prodrugs of anti-inflammatory carboxylic acids for improved delivery trough the skin. J. Pharm. Sci., 73, 1734–1737.

    Article  PubMed  CAS  Google Scholar 

  85. Wiegrebe W., Retzow A., Plumier E., Ersoy N., Garbe A., Faro H.P., Kunert R. (1984): Dermal absorption and metabolism of the antipsoriatic drug dithranol triacetate. Arzneim. Forsch., 34, 48–51.

    CAS  Google Scholar 

  86. Powell M.F., Magill A., Becker A.R., Kenley R.A., Chen S., Visor G.C. (1988): Non — steroidal anti-psoriatic prodrugs. II. Citric acid stabilization of lonapalene in various alcohol media and ointment formulation. Int. J. Pharm., 44, 225–234.

    Article  CAS  Google Scholar 

  87. Mukai E., Arase K., Hashida M., Sezaki H. (1985): Enhanced delivery of mitomycin C prodrugs through the skin. Int. J. Pharm., 25, 95–103.

    Article  CAS  Google Scholar 

  88. Hashida M., Mukai E., Kimura T., Sezaki H. (1985): Enhanced delivery of mitomycin C derivatives through hairless mouse and rat skins. J. Pharm. Pharmacol., 37, 542–544.

    PubMed  CAS  Google Scholar 

  89. Bundgaard H., Hoelgaard A., Mollgaard B. (1983): Leaching of hydrolytic enzymes from human skin in cutaneous permeation studies as determined with metrodinazole and 5-fluorouracil prodrugs. Int. J. Pharm., 15, 285–292.

    Article  CAS  Google Scholar 

  90. Johansen M., Mollgaard B., Wotton P.K., Larsen C., Hoelgaard A. (1986): In vitro evaluation of dermal prodrug delivery — Transport and bioconversion of a series of aliphatic esters of metronidazole. Int. J. Pharm., 32, 199–206.

    Article  CAS  Google Scholar 

  91. Koch S.A.M., Sloan K.B. (1987): N-Mannich base derivatives of 5-fluorocytosine: a prodrug approach to improve topical delivery. Int. J. Pharm., 35, 243–252.

    Article  CAS  Google Scholar 

  92. Sato K., Sugibayashi K., Morimoto Y. (1988): Effect and mode of action of aliphatic esters on the in vitro skin permeation of nicorandil. Int. J. Pharm., 43, 31–40.

    Article  CAS  Google Scholar 

  93. Bucks D.A.W. (1984): Skin stucture and metabolism: Relevance to the design of cutaneous therapeutics. Pharm. Res., 1, 148–153.

    Article  Google Scholar 

  94. McLure D.A. (1975): The effect of a pro-drug of epinephrine (dipivaloyl epinephrine) in glaucoma — General pharmacology, toxicology, and clinical experiance. In: Pro-Drugs as Novel Drug Delivery Systems, T. Higuchi & V.J. Stella, eds. American Chemical Society, Washington DC, pp. 224–235.

    Chapter  Google Scholar 

  95. Hussain M.A., Truelove J.E. (1976): Prodrug approaches to enhancement of physicochemical properties of drugs. IV. Novel epinephrine prodrug. J. Pharm. Sci., 65, 1510–1512.

    Article  PubMed  CAS  Google Scholar 

  96. Bodor N., Visor G. (1984): Formation of adrenaline in the irisciliary body from adrenalone diesters. Exp. Eye Res., 38, 621–626.

    Article  PubMed  CAS  Google Scholar 

  97. Bodor N., Visor G. (1984): Improved delivery through biological membranes. XVIII. A site specific chemical delivery system as a short — acting mydriatic agent. Pharm. Res., 1, 168–173.

    Article  Google Scholar 

  98. Bito L.Z. (1984): Comparison of the ocular hypotensive efficacy of eicosanoids and related compounds. Exp. Eye Res., 38, 181–194.

    Article  PubMed  CAS  Google Scholar 

  99. Bundgaard H., Falch E., Larsen C., Mosher G.L., Mikkelson T.J. (1985): Pilocarpic acid ester as novel sequentially labile pilocarpine prodrugs for improved ocular delivery. J. Med. Chem., 28, 979–981.

    Article  PubMed  CAS  Google Scholar 

  100. Bundgaard H., Falch E., Ursen C., Mikkelson T.J. (1986a): Pilocarpine prodrugs. I. Synthesis physicochemical properties and kinetics of lactonization of pilocarpic acid esters. J. Pharm. Sci., 75, 36–43.

    Article  PubMed  CAS  Google Scholar 

  101. Bundgaard H., Falch E., Larsen C., Mosher G.L., Mikkelson T.J. (1986b): Pilocarpine prodrugs II. Synthesis, stability, bioconversion and physicochemical properties of sequentially labile pilocarpine acid diesters. J. Pharm., Sci., 75, 775–783.

    Article  CAS  Google Scholar 

  102. Chien D.S., Schoenwald R.D. (1986): Improving the ocular absorption of phenylephrine. Biopharm. Drug Dispos., 7, 453–462.

    Article  PubMed  CAS  Google Scholar 

  103. Schoenwald R.D., Chien D.S. (1988): Ocular absorption and disposition of phenylephrine and phenylephrine oxazoiidine. Biopharm. Drug Dispos., 9, 527–538.

    Article  CAS  Google Scholar 

  104. Bundgaard H., Buur A., Chang S.C., Lee V.H.L. (1986c): Prodrugs of timolol for improved ocular delivery: Synthesis, hydrolysis kinetics and lipophilicity of various timolol esters. Int. J. Pharm., 33, 15–26.

    Article  CAS  Google Scholar 

  105. Duzman E., Chen C.G., Andreson J., Blumenthal M., Twizer H. (1982): Diacetyl derivative of nadolol I. Ocular pharmacology and short — term ocular hypotensive effect in glaucomatous eyes. Arch. Ophthalmol., 100, 1916–1919.

    PubMed  CAS  Google Scholar 

  106. Buur A., Bundgaard H., Lee V.H.L., (1988): Prodrugs of propranolol: Hydrolysis and intramolecular aminolysis of various propranolol esters and an oxazolidin-2-one-derivative. Int. J. Pharm., 42, 51–60.

    Article  CAS  Google Scholar 

  107. Bundgaard H., Buur A., Chang S.C., Lee V.H.L. (1988b): Timolol prodrugs: Synthesis, stability and lipophilicity of various alkyl, cycloalkyl and aromatic esters of timolol. Int. J. Pharm., 46, 77–88.

    Article  CAS  Google Scholar 

  108. Larsen J.D., Dundgaard H., Lee V.H.L. (1988): Prodrugs for the sulfonamide group. II. Water — soluble amino acid derivatives of N-methylsulfonamides as possible prodrugs. Int. J. Pharm., 47, 103–110.

    Article  CAS  Google Scholar 

  109. Larsen J.D., Bundgaard H. (1989): Prodrug forms for the sulfonamide group. III. Chemical and enzymatic hydrolysis of various N-sulfonyl imidates — A novel prodrug form for a suflonamide group or an ester function. Int. J. Pharm., 51, 27–38.

    Article  CAS  Google Scholar 

  110. Sinkula A.A. (1975): Application of the pro-drug approach to antibiotics. In: Pro-drugs as Novel Drug Delivery Systems, ACS Symposium Series, vol. 14, American Chemical Society, pp. 116–153.

  111. Stella V.J., Charman W.N.A., Naringrekar V.H. (1985): Prodrugs: Do they have advantages in clinical practice. Drugs, 29, 445–473.

    Article  Google Scholar 

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Authors and Affiliations

  1. School of Pharmacy, University of Geneva, Switzerland

    L. P. Balant, E. Doelker & P. Buri

  2. Department of Psychiatry, Geneva University Hospital, 1211, Geneva 4, Switzerland

    L. P. Balant

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  1. L. P. Balant
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  2. E. Doelker
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Balant, L.P., Doelker, E. & Buri, P. Prodrugs for the improvement of drug absorption via different routes of administration. Eur. J. Drug Metab. Pharmacokinet. 15, 143–153 (1990). https://doi.org/10.1007/BF03190197

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