Skip to main content
SpringerLink
Log in

Prodrugs

Do They Have Advantages in Clinical Practice?

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Summary

Prodrugs are pharmacologically inactive chemical derivatives of a drug molecule that require a transformation within the body in order to release the active drug. They are designed to overcome pharmaceutical and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug.

The scientific rationale, based on clinical, pharmaceutical and chemical experience, for the design of various currently used prodrugs is presented in this review. The examples presented are by no means comprehensive, but are representative of the different ways in which the prodrug approach has been used to enhance the clinical efficacy of various drug molecules.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  • Albert, A.: in Albert (Ed.) Selective Toxicity, pp. 21–62 (John Wiley, New York 1973).

  • Alibrandi, A.; Brani, G.; Ercoli, A.; Gardi, R. and Meli, A.: Factors influencing the biological activity of orally administered steroid compounds: Effect of the medium and of esterification. Endocrinology 66: 13–18 (1960).

    Article  PubMed  CAS  Google Scholar 

  • Anderson, J.A.; Davis, W.L. and Wei, C-P.: Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with that of the compound epinephrine. Investigative Ophthalmology and Visual Science 19: 817–823 (1980).

    PubMed  CAS  Google Scholar 

  • Andersgaard, H.; Finholt, P.; Gjermundsen, R. and Hoyland, T.: Rate studies on dissolution and enzymatic hydrolysis of chloramphenicol palmitate. Acta Pharmaceutica Suecica 11: 239–248 (1974).

    PubMed  CAS  Google Scholar 

  • Ariens, E.J.: Molecular pharmacology, a basis for drug design; in Jucker (Ed.) Progress in Drug Research, Vol. 10, pp. 429–529 (Birkhauser Verlag, Basel 1966).

    Google Scholar 

  • Ariens, E.J.: Modulation of pharmacokinetics by molecular manipulation; in Ariens (Ed.) Drug Design, Vol. II, pp. 1–127 (Academic Press, New York 1971).

    Google Scholar 

  • Ariens, E.J. and Simonis, A.M.: Drug action: Target tissue, dose-response relationships and receptors; in Torell et al. (Eds) Pharmacology and Pharmacokinetics, pp. 163–189 (Plenum Press, New York 1974).

    Google Scholar 

  • Atkinson, A.J. and Davison, R.: Diphenylhydantoin as an anti-arrhythmic drug. Annual Reviews of Medicine 25: 99–113 (1974).

    Article  CAS  Google Scholar 

  • Bey, P.: «Pro-drugs» activees specifiquement par le recepteurcible: Inhibition enzymatic du type kcal. Sciences et Techniques Pharmaceutiques 7: 171–176 (1978).

    CAS  Google Scholar 

  • Bodor, N.: Novel approaches for the design of membrane transport properties of drugs; in Roche (Ed.) Design of Biopharmaceutical Properties through Prodrugs and Analogs, pp. 98–135 (American Pharmaceutical Association, Washington, DC 1977).

    Google Scholar 

  • Bodor, N.: Novel approaches in prodrug design; in Bundgaard et al. Optimization of Drug Delivery, pp. 156–177 (Munksgaard, Copenhagen 1982).

    Google Scholar 

  • Bodor, N. and Brewster, M.E.: Improved delivery through biological membranes XV — Sustained brain delivery of berberine. European Journal of Medicinal Chemistry 18: 235–240 (1983).

    CAS  Google Scholar 

  • Bodor, N.; Shek, E. and Higuchi, T.: Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative. Science 190: 155–156 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Bodor, N.; Shek, E. and Higuchi, T.: Improved delivery through biological membranes. 1. Synthesis and properties of 1-methyl-1, 6-dihydropyridine, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride. Journal of Medicinal Chemistry 19: 102–107 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Bolme, P.; Dahlstrom, B.; Diding, N.A.; Flink, O. and Paalzo, L.: Ampicillin: Comparison of bioavailability and pharmacokinetics after oral and intravenous administration of three brands. European Journal of Clinical Pharmacology 10: 237–243 (1976).

    Article  CAS  Google Scholar 

  • Bundgaard, H.: Spectrophotometric determination of ampicillin sodium in the presence of its degradation and polymerization products. Journal of Pharmacy and Pharmacology 26: 385–392 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Bundgaard, H.: Novel bioreversible derivatives of amides, ureides, amines and other chemical entities not readily derivatizable; in Bundgaard et al. (Eds.) Optimization of Drug Delivery, pp. 178–198 (Munksgaard, Copenhagen 1982).

    Google Scholar 

  • Bundgaard, H.; Hansen, A.B. and Kofod, H. (Eds.): Optimization of Drug Delivery. Alfred Benzon Symposium 17 (Munksgaard, Copenhagen 1982).

  • Celmer, C.D.: Canadian Patent 779,315 (Feb 27, 1968).

    Google Scholar 

  • Clark, R.K. and Varner, E.L.: New esters of erythromycin. Antibiotics and Chemotherapy 7: 487–489 (1957).

    CAS  Google Scholar 

  • Davies, G.E. and Driver, G.W.: The antituberculous activity of ethylthiolesters with particular reference to diethyldithiol isophthalate. British Journal of Pharmacology 12: 434–437 (1957).

    CAS  Google Scholar 

  • Davies, G.E.; Driver, G.W.; Hoggarth, E.; Martin, A.R.; Paige, M.F.C.; Rose, F.L. and Wilson, B.R.: Studies in the chemotherapy of tuberculosis: Ethyl mercaptan and related compounds. British Journal of Pharmacology 11: 351–356 (1956).

    CAS  Google Scholar 

  • DeHaan, R.M.; Metzler, C.M.; Schellenberg, D. and Van-Denbosch, W.D.: Pharmacokinetic studies of clindamycin phosphate. Journal of Clinical Pharmacology 13: 190–209 (1973).

    PubMed  CAS  Google Scholar 

  • Digenis, G.A. and Swintosky, J.V.: Drug latentiation; in Gillette and Mitchell (Eds) Handbook of Experimental Pharmacology 28 (Part 3), pp. 86–112 (Springer, Berlin, Heidelberg, New York 1975).

    Google Scholar 

  • Dobrinska, M.R.; Furst, D.E.; Speigel, T.; Vincek, W.C.; Tompkins, R.; Duggan, D.E.; Davies, R.O. and Paulus, H.E.: Biliary secretion of sulindac and metabolites in man. Biopharmaceutics and Drug Disposition 4: 347–358 (1983).

    Article  CAS  Google Scholar 

  • Duggan, D.E.: Sulindac: Therapeutic implications of the prodrug/pharmacophore equilibrium. Drug Metabolism Reviews 12: 325–337 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Duggan, D.E.; Hare, L.E.; Ditzler, C.A.; Lei, B.W. and Kwan, K.C.: The disposition of sulindac. Clinical Pharmacology and Therapeutics 21: 326–335 (1977).

    PubMed  CAS  Google Scholar 

  • Duggan, D.E.; Hooke, K.F. and Hwang, S.S.: Kinetics of the tissue distributions of sulindac and metabolites. Drug Metabolism and Disposition 8: 241–246 (1980).

    PubMed  CAS  Google Scholar 

  • Edmondson, H.T.: Parenteral and oral clindamycin therapy in surgical infections — preliminary report. Annals of Surgery 178: 637–642 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Ehrnebo, M.; Nilsson, S. and Boreus, L.O.: Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man. Journal of Pharmacokinetics and Biopharmaceutics 7: 429–451 (1979).

    PubMed  CAS  Google Scholar 

  • Glazko, A.J.; Carnes, H.E.; Kazenko, A.; Wolf, L.M. and Reutner, T.P.: Succinic acid esters of chloramphenicol. Antibiotics Annual: 792–802 (1957–58).

    Google Scholar 

  • Glazko, A.J.; Edgerton, W.H.; Dill, W.A. and Lenz, W.R.: Chloromycetin palmitate: A synthetic ester of Chloromycetin. Antibiotics and Chemotherapy 2: 234–242 (1952).

    CAS  Google Scholar 

  • Gray, J.E.; Weaver, R.N.; Moran, J. and Feenstra, E.S.: The parenteral toxicity of clindamycin-2-phosphate in laboratory animals. Toxicology and Applied Pharmacology 27: 308–321 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Gray, L.H.; Conger, A.D.; Ebert, M.; Hornsey, S. and Scott, O.C.A.: The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. British Journal of Radiology 86: 638–648 (1953).

    Article  Google Scholar 

  • Gregoriadis, G.: Targetting of drugs. Nature 265: 407–411 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Gregoriadis, G. (Ed.): Drug Carriers in Biology and Medicine (Academic Press, New York 1979).

    Google Scholar 

  • Gruber, J.C.M.; Stephens, V.C. and Terrill, P.M.: Propoxyphene napsylate: Chemistry and experimental design. Toxicology and Applied Pharmacology 19: 423–426 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Harper, N.J.: Drug latentiation. Journal of Medicinal and Pharmaceutical Chemistry 1: 467–500 (1959).

    Article  PubMed  CAS  Google Scholar 

  • Harper, N.J.: Drug latentiation. Progress in Drug Research 4: 221–294 (1962).

    CAS  Google Scholar 

  • Higuchi, T. and Stella, V. (Eds.): Pro-drugs as Novel Drug Delivery Systems (American Chemical Society, Washington, DC 1975).

    Google Scholar 

  • Ho, N.F.H.; Park, J.Y.; Morozowich, W. and Higuchi, W.I.: Physical model approach to the design of drugs with improved intestinal absorption; in Roche (Ed.) Design of Biopharmaceutical Properties through Prodrugs and Analogs, pp. 136–227 (American Pharmaceutical Association, Washington, DC 1977).

    Google Scholar 

  • James, K.C.; Nichols, P.J. and Roberts, M.: Biological half-lives of [4–14C] testosterone and some of its esters after injection into the rat. Journal of Pharmacy and Pharmacology 21: 24–27 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen, A.: Pharmacokinetic studies on flupenthixol decanoate, a depot neuroleptic of the thioxanthene group. Drug Metabolism Reviews 8: 235–250 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Juliano, R.L. (Ed.): Drug Delivery Systems: Characteristics and Biomedical Applications (Oxford University Press, New York 1980).

    Google Scholar 

  • Krish, K.: Carboxylic ester hydrolases; in Boyer (Ed.) The Enzymes, Vol. V, pp. 43–69 (Academic Press, New York 1971).

    Google Scholar 

  • Kupchan, S.M.; Casy, A.F. and Swintosky, J.V.: Drug latentiation: Synthesis and preliminary evaluation of testosterone derivatives. Journal of Pharmaceutical Sciences 54: 514–524 (1965).

    Article  PubMed  CAS  Google Scholar 

  • Kyncl, J.J.; Minard, R.N. and Jones, P.H.: L-γ-glutamyl dopamine, an oral dopamine prodrug with renal selectivity; in Impsand and Schwartz (Eds.) Peripheral Dopaminergic Receptors, pp. 369–380 (Pergamon Press, New York 1979).

    Google Scholar 

  • Loo, J.C.K.; Foltz, E.L.; Wallick, H. and Kwan, K.C.: Pharmacokinetics of pivampicillin and ampicillin in man. Clinical Pharmacology and Therapeutics 16: 35–43 (1974).

    PubMed  CAS  Google Scholar 

  • Magni, L.; Sjoberg, G.; Sjovall, J. and Wessman, J.: Clinical pharmacological studies with bacampicillin; in Williams and Geddes (Eds.) Chemotherapy, Vol. 5, pp. 109–114 (Plenum, New York 1976).

    Google Scholar 

  • Mandell, A.I.; Stentz, F. and Kitabchi, A.B.: Dipivalyl epinephrine: A new prodrug in the treatment of glaucoma. Ophthalmology 85: 268–275 (1978).

    PubMed  CAS  Google Scholar 

  • McClure, D.A.: The effect of a pro-drug of epinephrine (dipivalyl epinephrine) in glaucoma — general pharmacology, toxicology and clinical experience; in Higuchi and Stella (Eds.) Pro-drugs as Novel Drug Delivery Systems, pp. 224–235 (American Chemical Symposium Series, Washington, DC 1975).

    Chapter  Google Scholar 

  • McEvoy (Ed.): American Hospital Formulary Service, Vol. 8, p. 24 (American Society of Hospital Pharmacists, Washington, DC 1974).

    Google Scholar 

  • Melby, J.C. and St Cyr, M.: Comparative studies on absorption and metabolic disposal of water-soluble corticosteroid esters. Metabolism 10: 75–82 (1961).

    PubMed  CAS  Google Scholar 

  • Morozowich, W.; Sinkula, A.A.; Karnes, H.A.; MacKellar, F.A.; Lewis, C.; Stern, K.F. and Rowe, E.L.: Synthesis and bioactivity of lincomycin-2-phosphate. Journal of Pharmaceutical Sciences 58: 1485–1489 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Morozowich, W.; Sinkula, A.A.; MacKellar, F.A. and Lewis, C.J.: Synthesis and bioactivity of lincomycin-2-monoesters. Journal of Pharmaceutical Sciences 62: 1102–1105 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Murphy, H.W.: Esters of erythromycin. Antibiotics Annual: 500–521 (1953–54).

    Google Scholar 

  • Nahata, M.C. and Powell, D.A.: Bioavailability and clearance of chloramphenicol after intravenous chloramphenicol succinate. Clinical Pharmacology and Therapeutics 30: 368–372 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Notari, R.E.: Prodrug design. Pharmacology and Therapeutics 14: 25–53 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Pang, K.S. and Gillette, J.R.: Kinetics of metabolite formation and elimination in the perfused rat liver preparation: Differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin. Journal of Pharmacology and Experimental Therapeutics 207: 178–194 (1978).

    PubMed  CAS  Google Scholar 

  • Redwood, D.: Conservative treatment of chronic heart block. British Medical Journal 1: 26–29 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Repta, A.J.; Hageman, M.J. and Patel, J.P.: Enol esters as potential prodrugs. IV. Enhanced delivery of the quaternary species coralyne to rat brain using 6′-acetylpapaverin and its enol esters as prodrugs. International Journal of Pharmaceutics 10: 239–248 (1982).

    Article  CAS  Google Scholar 

  • Roche, E.B. (Ed.): Design of Biopharmaceutical Properties through Prodrugs and Analogs (American Pharmaceutical Association, Washington, DC 1977a).

    Google Scholar 

  • Roche, E.B.: Structural aspects of selective distribution; in Roche (Ed.) Design of Biopharmaceutical Properties through Prodrugs and Analogs, pp. 27–46 (American Pharmaceutical Association, Washington, DC 1977b).

    Google Scholar 

  • Saari, W.S.; Freeman, M.B.; Hartman, R.D.; King, S.W.; Raab, A.W.; Randall, W.C.; Engelhardt, E.L.; Hirschmann, R.; Rosegay, A.; Ludden, C.T. and Scriabine, A.: Synthesis and antihypertensive activity of some ester progenitors of methyldopa. Journal of Medicinal Chemistry 21: 746–753 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Schwartz, M.A. and Hayton, W.I.: Relative stability of hetacillin and ampicillin in solution. Journal of Pharmaceutical Sciences 61: 906–909 (1972).

    Article  PubMed  CAS  Google Scholar 

  • 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-methylpyridinium-2-carbaldoxime chloride. J. Med. Chem. 19: 108–112 (1976a).

    Article  PubMed  CAS  Google Scholar 

  • 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. Journal of Medicinal Chemistry 19: 113–117 (1976b).

    Article  PubMed  CAS  Google Scholar 

  • Shen, T-S. and Winter, C.A.: Chemical and biological studies on indomethacin, sulindac and their analogs; in Harper and Simmonds (Eds) Advances in Drug Research, Vol. 12, pp. 89–246 (Academic Press, New York 1977).

    Google Scholar 

  • Simon, C.; Malerczyk, V. and Klans, M.: Absorption of bacampicillin and ampicillin and penetration into body fluids in healthy volunteers. Scandinavian Journal of Infectious Diseases 14 (Suppl.): 228–235 (1978).

    PubMed  CAS  Google Scholar 

  • Sinkula, A.: Prodrug approach in drug design. Annual Reports in Medicinal Chemistry 10: 306–316 (1975).

    Article  CAS  Google Scholar 

  • Sinkula, A.A.: Perspective on prodrugs and analogs in drug design; in Roche (Ed.) Design of Biopharmaceutical Properties through Prodrugs and Analogs, pp. 1–17 (American Pharmaceutical Association, Washington, DC 1977).

    Google Scholar 

  • Sinkula, A.A.: Methods to achieve sustained drug delivery — The chemical approach; in Robinson (Ed.) Sustained and Controlled Release Drug Delivery Systems, pp. 411–555 (Marcel Dekker, New York 1978).

    Google Scholar 

  • Sinkula, A.A. and Lewis, C.: Chemical modifications of lincomycin: Synthesis and bioactivity of selected 2,7-dialkylcarbonate esters. Journal of Pharmaceutical Sciences 62: 1757–1760 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Sinkula, A.; Morozowich, W. and Rowe, E.L.: Chemical modification of clindamycin: Synthesis and evaluation of selected esters. Journal of Pharmaceutical Sciences 62: 1106–1111 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Sinkula, A. and Yalkowsky, S.: Rationale for design of biologically reversible drug derivatives: Prodrugs. Journal of Pharmaceutical Sciences 64: 181–210 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Sjovall, J.; Magni, L. and Bergan, T.: Pharmacokinetics of bacampicillin compared with those of ampicillin, pivampicillin and amoxicillin. Antimicrobial Agents and Chemotherapy 13: 90–96 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Stella, V.J.: Chemical modification of drugs to overcome pharmaceutical problems. Australian Journal of Pharmaceutical Sciences NS2: 57–63 (1973).

    Google Scholar 

  • Stella, V.: Prodrugs: An overview and definition; in Higuchi and Stella (Eds.) Pro-drugs as Novel Drug Delivery Systems, pp. 1–115 (American Chemical Society, Washington, DC 1975).

    Chapter  Google Scholar 

  • Stella, V.J.: Drug substances in particular prodrugs: Problems and methods of approach; in Polderman (Ed.) Formulation and Preparation of Dosage Forms, pp. 91–111 (Elsevier/North-Holland, Amsterdam 1977).

    Google Scholar 

  • Stella, V.J. and Himmelstein, K.J.: Prodrugs and site specific delivery. Journal of Medicinal Chemistry 23: 1275–1282 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Stella, V.J. and Himmelstein, K.J.: Critique of prodrugs and site specific delivery; in Bundgaard et al. (Eds) Optimization of Drug Delivery — Alfred Benzon Symposium 17, pp. 134–155 (Munksgaard, Copenhagen 1982).

    Google Scholar 

  • Stewart, G.T.: Macromolecular residues contributing to the allergenicity of penicillins and cephalosporins. Antimicrobial Agents and Chemotherapy 7: 543–549 (1967).

    PubMed  CAS  Google Scholar 

  • Stewart, G.T.: Proteinaceous and polymeric residues in β-lactam antibiotics and bacitracins. Antimicrobial Agents and Chemotherapy 8: 128–135 (1968).

    PubMed  CAS  Google Scholar 

  • Tanaka, T.; Kobayashi, H.; Okumura, K.; Muranishi, S. and Sezaki, H.: Intramuscular absorption of drugs from oily solutions in the rat. Chemical and Pharmaceutical Bulletin 22: 1275–1284 (1974).

    Article  CAS  Google Scholar 

  • Theeuwes, F.: Elementary osmotic pumps. Journal of Pharmaceutical Sciences 64: 1987–1991 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Vane, J.R.: in Robinson and Vane (Eds) Prostaglandin Synthetase Inhibitors: Their Effects on Physiological Functions and Pathological States, p. 155 (Raven Press, New York 1974).

  • Varia, S.A.; Schuller, S.; Sloan, K.B. and Stella, V.J.: Phenytoin prodrugs. III: Water soluble prodrugs for oral and/or parenteral use. Journal of Pharmaceutical Sciences 73: 1068–1073 (1984a).

    Article  PubMed  CAS  Google Scholar 

  • Varia, S.A.; Schuller, S. and Stella, V.J.: Phenytoin prodrugs. IV: Chemical stability of various 3-(hydroxymethyl)-phenytoin esters. Journal of Pharmaceutical Sciences 73: 1074–1079 (1984b).

    Article  PubMed  CAS  Google Scholar 

  • Varia, S.A. and Stella, V.J.: Phenytoin prodrugs. V: In vivo evaluation of some water soluble phenytoin prodrugs in dogs. Journal of Pharmaceutical Sciences 73: 1080–1086 (1984c).

    Article  PubMed  CAS  Google Scholar 

  • Varia, S.A. and Stella, V.J.: Phenytoin prodrugs. VI: In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats. Journal of Pharmaceutical Sciences 73: 1087–1090 (1984d).

    Article  PubMed  CAS  Google Scholar 

  • Vickers, S.; Duncan, C.A.; White, S.D.; Breault, G.O.; Royds, K.B.; deSchepper, P.J. and Tempero, K.F.: Evaluation of succinoimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog and rat. Drug Metabolism and Disposition 6: 640–646 (1978).

    PubMed  CAS  Google Scholar 

  • Villeneuve, A.; Pires, A.; Jus, A.; Lachance, R. and Drolet, A.: A long-term pilot study of pipothiazine palmitate in chronic schizophrenia. Current Therapeutic Research — Clinical and Experimental 14: 696–706 (1972).

    CAS  Google Scholar 

  • Wilk, S.; Mizoguchi, H. and Orlowski, M.: γ-Glutamyl dopa: A kidney specific dopamine precursor. Journal of Pharmacology and Experimental Therapeutics 206: 227–232 (1978).

    PubMed  CAS  Google Scholar 

  • Yale, H.L.: Esters of 4[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazine ethanol and related compounds as long-acting antipsychotic agents. Synthesis of the 1-adamantsoate, the first crystalline base 4. Journal of Medicinal Chemistry 20: 302–304 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Yale, H.L.: The long acting neuroleptics: A retrospective appraisal. Drug Metabolism Reviews 8: 251–264 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Yalkowsky, S.H. and Morozowich, W.: A physical chemical basis for the design of orally active prodrugs; in Ariens (Ed.) Drug Design, Vol. IX, pp. 121–185 (Academic Press, New York 1980).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of Kansas, School of Pharmacy, Lawrence, KS, 66045, USA

    V. J. Stella, W. N. A. Charman & V. H. Naringrekar

Authors
  1. V. J. Stella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. N. A. Charman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. H. Naringrekar
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stella, V.J., Charman, W.N.A. & Naringrekar, V.H. Prodrugs. Drugs 29, 455–473 (1985). https://doi.org/10.2165/00003495-198529050-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-198529050-00002

Keywords

Search

Navigation