Abstract
In recent years several biologically active peptides have been discovered, including peptides consisting of only two or three amino acids, and most certainly, the development of peptide drugs will be a major area in drug research in the future. The application of peptides as clinically useful drugs is, however, seriously hampered due to substantial delivery problems. Peptides are readily degraded by enzymes in the gastrointestinal system and are absorbed poorly, making the oral route a poor way of administration (Wiedhaup, 1981). Pronounced degradation of peptides does also occur at routes of administration other than oral, such as the ocular, nasal, buccal, rectal and vaginal routes (Okada et al., 1982; Kimura, 1984; Lee et al., 1985; Stratford and Lee, 1986). Another factor contributing to the poor bioavailability of peptides is most certainly the non-lipophilicity of peptides. Furthermore, peptides suffer from metabolic lability arising from hydrolysis by plasma and tissue peptidases and even simple parenteric administration is problematic, due to the short half-lives of the peptides once they reach the bloodstream. Several peptides also suffer from systemic transport problems in that they do not readily penetrate cell membranes to reach the receptor biophase or cross the blood-brain barrier (Farmer and Ariƫns, 1982; Meisenberg and Simmons, 1983).
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References
Alexander, J. 1985, (Acyloxyalkoxy)carbony1 derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs, their preparation and pharmaceutical compositions containing said derivatives, Eur. Pat. Appl., No. 130, 119.
Baker, G.B., Coutts, R.T., Nazarali, A.J., Danielson, T.J., and Rubens, M., 1984, Carbamate prodrugs of phenylethylamines: A neurochemical investigation, Proc. West. Pharmacol. Soc., 27: 523.
Baldwin, J.J., Denny, G. H., Ponticello, G.S., Sweet, C.S. and Stone, C.A., 1982, Tyrosine progenitors as antihypertensive agents, Eur. J. Med. Chem., 17: 297.
Belke, C.J., Su, S.C.K., and Shafer, J.A., 1971, Imidazole-catalyzed displacement of an amine from an amide by a neighboring hydroxyl group. A model for the acylation of chymotrypsin, J. Am. Chem. Soc., 93: 4552.
Bodin, N.O., Ekstrƶm, B., Forsgren, U., Jalar, L.P., Magni, L. Ramsey, C.H., and Sjƶberg B., 1975, Bacampicillin: A new orally well-absorbed derivative of ampicillin, Antimicrob. Agents. Chemother., 8: 518.
Bodor, N., Sloan, K.B., Higuchi, T., and Sasahara, K., 1977, Improved delivery through biological membranes. 4. Prodrugs of L-Dopa, J. Med. Chem., 20: 1435.
Bodor, N., Zupan, J., and Selk, S., 1980, Improved delivery through biological membranes VII. Dermal delivery of chromoglycic acid (cromolyn) via its prodrugs, Int. J. Pharm., 7: 64.
Bodor, N., Sloan, K.B., Kminski, J.J., Shih, C., and Pogani, S., 1983, A convenient synthesis of (acyloxy)alkyl Ī±-ethers of phenols, J. Org. Chem., 48: 5280.
Bundgaard, H., 1976, Polymerization of penicillins: kinetics and mechanisms of di-and polymerization of ampicillin in aqueous solution, Acta Pharm. Suec., 13: 9.
Bundgaard, H., 1982, Novel bioreversible derivatives of amides, imides, ureides, amines and other chemical entities not readily derivatizable, in: āOptimization of drug deliveryā, H. Bundgaard, A.B. Hansen and H. Kofod eds., Munksgaard, Copenhagen.
Bundgaard, H., 1985a, Design of prodrugs: Bioreversible derivatives for various functional groups and chemical entities, in: āDesign of prodrugsā, H. Bundgaard ed., Elsevier Biomedical Press, Amsterdam.
Bundgaard, H., 1985b, The formation of prodrugs of amines, amides, ureides and imides. Methods in Enzymology 112:347.
Bundgaard, H. and Johansen, M., 1980a, Pro-drugs as drug delivery systems. IV. N-Mannich bases as potential novel pro-drugs for amides, ureides, amines, and other NH-acidic compounds, J. Pharm. Sci. 69:44.
Bundgaard, H. and Johansen, M., 1980b, Pro-drugs as drug delivery systems. X. N-Mannich bases as novel pro-drug candidates for amides, imides, urea derivatives, amines and other NH-acidic compounds. Kinetics and mechanisms of decomposition and structure-reactivity relationships, Arch. Pharm. Chem., Sci. Ed. 8:29.
Bundgaard, H. and Johansen, M., 1980c, Pro-drugs as drug delivery systems. XV. Bioreversible derivatization of phenytoin, acetazolamide, chlorzoxazone and various other NH-acidic compounds by N-aminome-thylation to effect enhanced dissolution rates, Int. J. Pharm. 7:129.
Bundgaard, H. and Johansen, M. 1981, Hydrolysis of N-Mannich bases and its consequences for the biological testing of such agents, Int. J. Pharm., 9: 7.
Bundgaard, H. and Johansen, M., 1981, Pro-drugs as drug delivery systems. XVIII. Bioreversible derivatization of allopurinol by N-aminomethylation to effect enhanced dissolution rates, Acta Pharm. Suec., 18: 129.
Bundgaard, H. and Johansen, M., 1982, Prodrugs as drug delivery systems. XIX. Bioreversible derivatization of aromatic amines by formation of N-Mannich bases with succinimide, Int. J. Pharm., 8: 183.
Bundgaard, H., KlixbĆ¼ll, U., and Falch, E., 1986, Prodrugs as drug delivery systems. 43. O-Acyloxymethyl salicylamide N-Mannich bases as double prodrug forms for amines, Int. J. Pharm., 29: 19.
Cain, B.F., 1976, 2-Acyloxymethylbenzoic acids. Novel amine protective functions providing amides with the lability of esters, J. Org. Chem., 41: 2029.
Caldwell, H.C., Adams, H.J., Jones, R.G., Mann, W.A., Dittert, L.W., Chong, C.W., and Swintosky, J.V., 1971, Enamine prodrugs J. Pharm. Sci., 60: 1810.
Cardinaux, F. and Brenner, M., 1973, N, Nā-Alkylidenpeptide: Peptidsynthese-Nebenprodukte bei Einwirkung von Carbonylverbindungen, Helv. Chim. Acta, 56: 339.
Chiong, K.N.G., Lewis, S.D., and Shafer, J.A., 1975, Rationalization of the rate of the acylation step in chymotrypsin-catalyzed hydrolysis of amides, J. Am. Chem. Soc., 97: 418.
Clayton, J.P., Cole, M., Elson, S.W., and Ferres, H., 1974, BRL.8988 (talampicillin), a well-absorbed oral form of ampicillin. Antimicrob. Agents Chemother., 5: 670.
Daehne, W.v., Frederiksen, E., Gundersen, E., Lund, F., MĆørch, P., Petersen, H.J., Roholt, K., Tybring, L., and Godtfredsen, W.O., 1970, acyloxymethyl esters of ampicillin, J. Med. Chem., 13: 607.
Digenis, G.A. and Swintosky, J.V., 1975, Drug latentiation, Handbook of Experimental Pharmacology, 28/3:86.
Dixon, K. and Greenhill, J.V., 1974, A study of the rates of hydrolysis of certain enaminones, J. Chem. Soc. Perkin II, 164.
Dobrinska, M.R., Kukovetz, W., Beubler, E., Leidy, H.L., Gomez, H.J., Demetriades, J., and Bolognese, J.A., 1982, Pharmacokinetics of the pivaloyloxyethyl (POE) ester of methyldopa, a new prodrug of methyldopa, J. Pharmacokin. Biopharm., 10: 587.
Farmer, P.S. and Ariƫns, E.J., 1982, Speculations on the design on non-peptidic peptidomimetics, Trends Pharm. Sci., 3: 362.
Farquhar, D., Srivastva, D.N., Kuttesch, N.J., and Saunders, P.P., 1983, Biologically reversible phosphate-protective groups, J. Pharm. Sci., 72: 324.
Fife, T.H. and Benjamin, B.M., 1974, Intramolecular general base-catalyzed alcoholysis of amides, J. Chem. Soc, Chem. Comm. 525.
Ferres, H., 1983, Pro-drugs of Ć-lactam antibiotics, Drugs of Today, 19: 499.
Hardcastle, G.A., Johnson, D.A., Panetta, C.A., Scott, A.I., and Sutherland, S.A., 1966, The preparation and structure of hetacillin, J. Org. Chem., 31: 897.
Hruby, V.H., Yamashiro, D., Vigneaud, V. du, 1968, The structure of acetone-oxytocin with studies on the reaction of acetone with various peptides. J. Am. Chem. Soc., 90: 7106.
Jansen, A.B.A. and Russell, T.J., 1965, Some novel penicillin derivatives, J. Chem. Soc. 2127.
Jemal, M., Ivashkiv, E., Ribick, M., and Cohen, A.I., 1985, Determination of SQ 27,519, The active phosphinic acid-carboxylic acid of the prodrug SQ 28,555, in human serum by capillary gas chromatography with nitrogen-phosphorus detection after a two-step derivatization, J.Chromatogr., 345: 299.
Jusko, W.J. and Lewis, G.P., 1973, Comparison of ampicillin and hetacillin pharmacokinetics in man, J. Pharm. Sci., 62: 69.
Johansen, M. and Bundgaard, H., 1980a, Pro-drugs as drug delivery system. XII. Solubility, dissolution and partitioning behaviour of N-Mannich bases and N-hydroxymethyl derivatives, Arch. Pharm. Chem., Sci. Ed. 8:141.
Johansen, M. and Bundgaard, H., 1980b, Pro-drugs as drug delivery systems. XIII. Kinetics of decomposition of N-Mannich bases of salicylamide and assessment of their suitability as possible pro-drugs for amines, Int. J. Pharm. 7:119.
Johansen, M. and Bundgaard, H., 1982, Pro-drugs as drug delivery systems. XXIV. N-Mannich bases as bioreversible lipophilic transport forms of ephedrine, phenethylamine and other amines, Arch. Pharm. Chem., Sci. Ed., 10: 111.
Kakeya, N., Nishimura, K.-I., Yoshimi, A., Nakamura, S., Nishizawa, S., Tamaki, S., Matsui, H., Kawamura, T., Kasai, M., and Kitae, K., 1984, Studies of prodrugs of cephalosporins. I. Synthesis of biological properties of glycyloxybenzoyloxymethyl and glycylaminobenzoyloxy-methyl esters of 7 Ć-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid, Chem. Pharm. Bull., 32: 692.
Kimura, T., 1984, Transmucosal absorption of small peptide drugs, Pharm. Int., 5: 75.
KlixbĆ¼ll, U. and Bundgaard, H., 1983, Prodrugs as drug delivery systems. XXIX. Imidazole-1-carboxylic acid esters of hydrocortisone and testosterone, Arch. Pharm. Chem., Sci. Ed., 11: 101.
KlixbĆ¼ll, U. and Bundgaard, H., Prodrugs as drug delivery systems. XXX. 4-Imidazolidinones as potential bioreversible derivatives for the Ī±-aminoamide moiety in peptides, Int. J. Pharm. 20:273.
KlixbĆ¼ll, U. and Bundgaard, H., 1985, Kinetics of reversible reactions of ampicillin with various aldehydes and ketones with formation of 4-Imidazolidinones, Int. J. Pharm., 23: 163.
Kupchan, S.M. and Isenberg, A.C., 1967, Drug latentiation. III. Labile amide derivatives of normeperidine, J. Med. Chem., 10: 960.
Kyncl, J.J., Minard, F.N., and Jones, P.H., 1979, L-Ī±-Glutamyl dopamine, an oral dopamine prodrug with renal selectivity, Adv. Biosci., 20: 369.
Larmour, I., Jackson, B., Cubela, R. and Johnston, C.I., 1985, Enalapril (MK421) activation in man: importance of liver status, Br. J. Clin. Pharmacol., 19: 701.
Larsen, J.D. and Bundgaard, H., 1986, Prodrugs as drug delivery systems. 49. Hydrolysis kinetics of enaminones derived from various amino acids and 1,3-diketones, keto-esters and keto-amides, Arch. Pharm. Chem., Sci. Ed., 14: 52.
Lee, V.H.L., Stratfors, R.E., Carson, L.W., and Kashi, S.D., 1985, Effect of ocular aminopeptidases on ocular absorption of enkephalins, Invest. Ophthalmol. Vis. Sci. Suppl., 26: 106.
Loftsson, T. and Bodor, N., 1982, Synthesis and hydrolysis of some pivaloyloxymethyl and pivaloyl derivatives of phenolic compounds, Arch. Pharm. Chem., Sci. Ed., 10: 104.
Meisenberg, G. and Simmons, W.H., 1983, Peptides and the blood-brain barrier, Life Sci., 32: 2611.
Murakami, T., Tamauchi, H., Yamazaki, M., Kubo, K., Kamada, A., and Yata, N., 1981, Biopharmaceutical study on the oral and rectal administrations of enamine prodrugs of amino acid-like Ć-lactam antibiotics in rabbits, Chem. Pharm. Bull., 29: 1986.
Murakami, T., Yata, N., Tamauchi. H., Nakai, J., Yamazaki, M., and Kamada, A., 1981, Studies on absorption promotors for rectal delivery preparations. I. Promoting efficacy of enamine derivatives of amino acids for the rectal absorption of Ć-lactam antibiotics in rabbits, Chem. Pharm. Bull., 29: 1998.
Nielsen, N.M., and Bundgaard, H., 1986, Prodrugs as drug delivery systems. Part. 42. 2-Hydroxymethylbenzamides and 2-acyloxymethyl-benzamides as potential prodrug forms for amines, Int. J. Pharm., 29: 9.
Okada, H., Yamazaki, I., Ogawa, Y., Hirai, S., Yoshiki, T., and Mima, H.J., 1982, Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (Leuprolide) in rats I: Absorption by various routes and absorption enhancement, J. Pharm. Sci., 71: 1367.
Okuyama, T. and Schmir, G.L., 1972, Hydrolysis of 1-benzylimino-1,3-dihydroisobenzofuran. Implications for the mechanism of lactonization of 2-hydroxymethylbenzamides, J. Am. Chem. Soc. 94:8805.
Orlowski, M., Mizoguchi, H., and Wilk, S., 1979, N-Acyl-y-glutamyl derivatives of sulfamethoxazole as models of kidney-selective prodrugs, J. Pharmacol. Exp. Ther., 212: 167.
Pitman, I.H., 1981, Prodrugs of amides, imides and amines, Med. Res. Rev., 1: 189.
Rakhit, A. and Tipnis, V., 1984, Liquid-chromatographic determination of an angiotensin converting enzyme inhibitor, CGS 13945, and its active metabolite (CGS 13934) in plasma, Clin. Chem., 30: 1237.
Roche, E.B., ed., 1977, āDesign of biopharmaceutical properties through prodrugs and analogsā, Washington, D.C., American Pharmaceutical Association.
Saari, W.S., Freedman, M.B., Hartman, R.D., King, S.W., Raab, A.W., Randall, W.C., Engelhardt, E.L., Hirschman, R., Rosegay, A., Ludden, C.T., and Scriabine, A., 1978, Synthesis and antihypertensive activity of some ester progenitors of methyldopa, J. Med. Chem., 21: 746.
Saari, W.S., Halczenko, W., Cochran, D.W., Dobrinska, M.R., Vincek, W.C., Titus, D.C., Gaul, S.L., and Sweet, C.S., 1984, 3-Hydroxy-Ī±-methyltyrosine progenitors: Synthesis and evaluation of some (2-oxo-1,3-dioxol-4-yl)methylesters, J. Med. Chem., 27: 713.
Sakamoto, F., Ikeda, S., and Tsukamoto, G., 1984, Studies on prodrugs. II. Preparation and characterization of (5-substituted 2-oxo-1,3-dioxolen-4-yl)methyl esters of ampicillin, Chem. Pharm. Bull., 32: 2241.
Sakamoto, F., Ikeda, S., Kondo, H., and Tsukamoto, G., 1985, Studies on prodrugs. IV. Preparation and characterization of N-(5-substituted 2-oxo-1,3-dioxol-4-yl)methyl norfloxacin, Chem. Pharm. Bull., 33: 4870.
Sasaki, H., Mukai, E., Hashida, M., Kimura, T., and Sezaki, H., 1983, Development of lipophilic prodrugs of mitomycin C. I. Synthesis and antitumor activity of 1a-N-substituted derivatives with aromatic pro-moiety, Int. J. Pharm., 15: 49.
Sasaki, H., Mukai, E., Hashida, M., Kimura, T., and Sezaki, H., 1983, Development of lipophilic prodrugs of mitomycin C. II. Stability and bioactivation of 1a-N-substituted derivatives with aromatic pro-moiety, Int. J. Pharm., 15: 61.
Sasaki, H., Fukumoto, M. Hashida, M., Kimura, T., and Sezaki, H., 1983, Development of lipophilic prodrugs of mitomycin C. III. Physicochemical and biological properties of newly synthesized alkoxycarbonyl derivatives, Chem. Pharm. Bull., 31: 4083.
Schwartz, M.A. and Hayton, W.L., 1972, Relative stability of hetacillin and ampicillin in solution, J. Pharm. Sci., 61: 906.
Shiobara, Y., Tachibana, A., Sasaki, H., Watanabe, T., and Sado, T., 1974, Phthalidyl D-Ī±-aminobenzylpenicillinate hydrochloride (PC-183), a new orally active ampicillin ester. J. Antibiot., 27: 665.
Sinkula, A.A., 1975, Prodrug approach in drug design, Annual Reports in Medicinal Chemistry, 10: 306.
Sinkula, A.A. and Yalkowsky, S.H., 1975, Rationale for design of biologically reversible drug derivatives: Prodrugs, J. Pharm. Sci. 64:181.
Srivastva, D.N. and Farquhar, D., 1984, Bioreversible phosphate protective groups: Synthesis and stability of model acyloxymethyl phosphates, Bioorg. Chem., 12: 118.
Stella, V., 1975, Pro-drugs: An overview and definition, in: āPro-drugs as novel drug delivery systemsā, T. Higuchi and V. Stella, eds./ American Chemical Society, Washington, D.C.
Stratford, R.E. and Lee, V.H.L., 1986, Aminopeptidase activity in homogenates of various absorptive mucosae in the albino rabbit: implications in peptide delivery, Int. J. Pharm., 30: 73.
Summers, M.C., Gidley, M.J., and Sanders, J.K., 1980, āAcetaldehyde-enkephalinsā: elucidation of the structure of the acetaldehyde adducts of methionine-enkephalin and leucine-enkephalin, FEBS Lett., 111: 307.
Summers, M.C. and Lightman, S.L., 1981, A reaction of acetaldehyde with enkephalins and related peptides, Biochem. Pharmacol., 30: 1621.
Tipnis, V. and Rakhit, A., 1985, Determination of pentopril, an angiotensin converting enzyme inhibitor, and its active metabolite in urine, J. Chromatogr., 345: 396.
Todd, P.A. and Heel, R.C., 1986, Enalapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure, Drugs, 31: 198.
Verbiscar, A.J. and Abood, L.G., 1970, Carbamate ester latentiation of physiologically active amines, J. Med. Chem., 13: 176.
Vickers, S., Duncan, C.A.H., Ramjit, H.G., Dobrinska, M.R., Dollery, C.T., Gomez, H.J., Leidy, H.L., and Vincek, W.C., 1984, Metabolism of methyldopa in man after oral administration of the pivaloyloxyethyl ester, Drug Metab. Disp., 12: 242.
Wiedhaup, K., 1981, The stability of small peptides in the gastrointestinal tract, in: āTopics in Pharmaceutical Sciencesā, D.D. Breimer and P. Speiser, eds., Elsevier/North-Holland Biomedical Press, Amsterdam.
Wilk, S., Mizoguchi, H., and Orlowski, M., 1978, Ī³-Glutamyl Dopa: A kidney-specific dopamine precursor, J. Pharmacol. Exp. Ther., 206: 227.
Yamashiro, D., Aanning, H.L., and Vigneaud, V. du, 1965, Inactivation of oxytocin by acetone, Proc. Natl. Acad. Sci. U.S.A., 54: 166.
Zlojkowska, Z., Krasuka, H.J., and Pachecka, J., 1982/ Enzymatic hydrolysis of amino acid derivatives of benzocaine, Xenobiotica 12:359.
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Bundgaard, H. (1986). Bioreversible Derivatization of Peptides. In: Davis, S.S., Illum, L., Tomlinson, E. (eds) Delivery Systems for Peptide Drugs. NATO ASI Series, vol 125. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9960-6_4
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