Abstract
The term Prodrug is used to describe compounds which must undergo chemical transformation prior to exhibiting their pharmacologic or therapeutic action. The concept is not new since compounds such as acetylsalicylic acid (aspirin), as a prodrug of salicylic acid, and methenamine, as a prodrug of formaldehyde, were discovered in the late 19th century. The term “pro-drug or “pro-agent” was first used by Albert (1958) who suggested that this approach could be used to alter the properties of drugs, in a temporary manner, to increase their usefulness, and/or decrease associated toxicity.
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References
Albert, A., Chemical aspects of selective toxicity. Nature, 182 (1958) 421–423.
Albert, A., Selective Toxicity, 3rd Edn., John Wiley and Sons Inc., New York, N.Y., 1965, p. 63.
Albert, A., Selective Zbxicity, 5th ed., John Wiley, New York, 1973, pp. 21–26.
Ariens, E.J., Molecular pharmacology, a basis for drug design. In Jucker (Ed) Progress in Drug Research, Vol. 10, Birkhauser Verlag, Basel, 1966, pp. 429–529.
Ariens, E.J., Modulation of pharmacokinetics by molecular manipulation. In Ariens (Ed) Drug Design Volume II, Academic Press, New York, 1971, pp. 1–127.
Bodor, N., Shek, E. and Higuchi, T., Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative. Sci., 190 (1975) 155–156.
Bodor, N., Shek, E. and Higuchi, T., Improved delivery through biological membranes. 1. Synthesis and properties of 1-methyl-1,6-dihydropyridine, a prodrug of N-methylpyridinium-2-carbaldoxime chloride. J. Med. Chem., 19 (1976) 102–107.
Bodor, N., Novel approaches in prodrug design. In Bundgaard, Hansen and Kofod (Eds) Optimization of Drug Delivery, Munksgaard, Copenhagen, 1982, pp. 156–177.
Bodor, N. and Brewster, M.E., Improved delivery through biological membranes XV - Sustained brain delivery of berberine. Europ. Med. Chem., 18 (1983), 235–240.
Bundgaard, H., Novel bioreversible derivatives of amides, ureides, amines and other chemical entities not readily derivatizable, In Bundgaard, Hausen and Kofod (Eds) Optimization of Drug Delivery, Munksgaard, Copenhagen, (1982), pp. 178–198.
Digenis, G.A. and Swintosky, J.V., Drug latentiation, In Gillette and Mitchell (Eds) Handbook of Experimental Pharmacology, Vol. 28 (part 3), Springer-Verlag Berlin (1975) pp. 86–112.
Double, J.A. and Vbrkman, P., A new high-glucuronidase mouse tumor curable by aniline mustard therapy, Canc. Treat. Rept., 61 (1977) 909–911.
Duggan, D.E., Sulindac: Therapeutic implications of the prodrug/pharmacophore equilibrium. Drug Met. Rev., 12 (1981) 325–337.
Duggan, D.E., Hare, L.E., Ditzler, C.A., Lei, B.W. and Kwan, K.C., The disposition of sulindac. Clin, Pharmacol. Therap., 21 (1977) 326–335.
Friend, D.R. and Chang, G.W., A colon-specific drug delivery system based on drug glycosides and glycosidases of colonic bacteria. J. Med. Chem., 27 (1984) 261–266.
Fyfe, J.A., Keller, P.M., Furman, P.A., Miller, R.L. and Elion, G.B., Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J. Biol. Chem. 253 (1978) 8721–8727.
Goldman, P., Will there be a next generation of sulfasalazine? Gastroenterol., 83 (1982) 1138–1141.
Harper, N.J., Drug latentiation. J. Med. Pharm. Chem. 1 (1959) 467–500.
Harper, N.J., Drug latentiation. Prog. Drug Res. 4 (1962) 221–294.
Higuchi, T. and Stella, V. (Eds) Pro-drugs as NDvel Drug Delivery Systems, American Chemical Society, Washington, D.C. 1975.
Higuchi, T. (1984) personal communications.
Jewell, D.P. and Truelove, S.C., Disodium azodisalicylate in ulcerative. Lancet ii (1981) 1168.
Kyncl, J.J., Minard, R.N. and Jones, P.H., L-y-glutamyl dopamine, an oral dopamine prodrug with renal selectivity. In Impsand and Schwartz (Eds) Peripheral Dopaminergic Receptors, Pergamon Press, New York, (1979) pp. 369–380.
Louenberg, W., Weissbach, H. and Udenfriend, S., Aromatic L-amino acid decarboxylase. J. Biol. Chem. 237 (1962) 89–93.
Notari, R.E., Prodrug design. Pharmacol. Therap. 14 (1981) 25–53.
Orlowski, M., Mizoguchi, H. and Wilk, S., N--Acyl-y-glutamyl derivatives of sulfamethoxazole as models of kidney-selective prodrugs. J. Pharmacol. Exp. Therap., 212 (1980) 167–172.
Pipkin, J.D. and Stella, V.J., Thiamine whole blood pharmacokinetics in rats using both a specific 5S-thiamine liquid scintillation assay and the thiochrome fluorescence assay. J. Pharm. Sci. 67 (1978) 818–821.
Poste, G. and Kirsch, R., Site specific drug delivery in cancer therapy. Biotechnology 1 (1983) 869–878.
Roche, E.B. (ED) Design of Biopharmaceutical Properties Through Prodrugs and Analogs. American Pharmaceutical Association, Washington, D.C., 1977.
Shashoua, V.V. Jacob, J.N., Ridge, R., Campbell, A. and Baldessarini, R.J., y-Aminobutyric acid esters. 1. Synthesis, brain uptake, and pharmacological studies of aliphatic and steroidal esters of y-aminobutyric acid. J. Med. Chem. 27 (1984) 659–664.
Shek, E., Higuchi, T. and Bodor, N. Improved delivery through biological membranes. 2. Distribution, excretion and metabolism of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, a prodrug of N-methylpyridiniumr-2-carbaldoxime chloride. J. Med. Chem. 19 (1976a) 108–112.
Shek, E., Higuchi, T. and Bodor, N., Improved delivery through biological membranes. 3. Delivery of N-methylpyridinium-2-carbaldoxime chloride through the blood brain barrier in its dihydropyridine pro-drug form. J. Med. Chem. 19 (1976b) 113–117.
Shen, T-S., and Winter, C.A., Chemical and biological studies on indomethacin, sulindac and their analogs. In Harper and Simonds (Eds) Advances in Drug Research Vol. 12, Academic Press, New York, 1977, pp. 89–246.
Shindo, H., Kornai, T. and Kawai, K., Mechanism of intestinal absorption and brain uptake of L-5-hydroxytryptophan in rats, as compared to those of L-3,4-dihydroxyphenyl-alanine. Chem. Pharm. Bull. 25 (1977) 1417–1425.
Sinkula, A., Prodrug approach in drug design. Ann. Rep. Med. Chem. 10 (1975) 306–316.
Sinkula, A. and Yalkowsky, S. Rationale for design of biologically reversible drug derivatives: Prodrugs. J. Pharm. Sci. 64 (1975) 181–210.
Stella, V.J., Drug substances in particular prodrugs: Problems and methods of approach. In Polderman (Ed) Formulation and Preparation of Dosage Forms, Elsevier/North-Holland, Amsterdam, 1977, pp. 91–111.
Stella, V.J. and Himmelstein, K.J., Prodrugs and site specific delivery. J. Med. Chem. 23 (1980) 1275–1282 (1980).
Stella, V.J. and Himmelstein, K.J., Critique of prodrugs and site specific delivery. In Bundgaard, Hansen and Koford (Eds) Optimization of Drug Delivery-Alfred Benzon Symposium 17, Munksgaard, Copenhagen, 1982, pp. 134–155.
Ulm, E.H., Enalapril maleate (MK 421), a potent nonsulfhydryl angiotension-converting enzyme inhibitor: Absorption, disposition and metabolise in man. Drug Metab. Rev. 14 (1983) 99–110.
Wilk, S., Mizoguchi, H. and Orlowski, M., y-Glutamyl dopa: A kidney specific dopamine precursor. J. Pharmacol. Exp. Therap. 206 (1978) 227–232.
Workman, P. and Double, J.A., Drug latentiation in cancer chemotherapy, Blamed. 28 (1978) 255–262.
Yalkowsky, S.H. and Morozowich, W., A physical chemical basis for the design of orally active prodrugs, In Ariens (Ed) Drug Design Vol. IX, Academic Press, New York, 1980, pp. 121–185.
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Stella, V.J., Himmelstein, K.J. (1985). Prodrugs: A Chemical Approach to Targeted Drug Delivery. In: Borchardt, R.T., Repta, A.J., Stella, V.J. (eds) Directed Drug Delivery. Experimental Biology and Medicine, vol 7. Humana Press. https://doi.org/10.1007/978-1-4612-5186-6_14
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DOI: https://doi.org/10.1007/978-1-4612-5186-6_14
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