Enzymatic Barriers to Peptide and Protein Absorption and the Use of Penetration Enhancers to Modify Absorption

  • Vincent H. L. Lee
Part of the NATO ASI Series book series (NSSA, volume 125)

Abstract

The mammalian body possesses several extremely efficient mechanisms to restrict the entry of macromolecules. These include the presence of various epithelia that are poorly absorptive, the presence of significant levels of enzymatic activity at various locations between the point of entry into the systemic circulation and the target site of a peptide or protein, the availability of multiple enzymes to degrade peptides and proteins at a given location, and varying levels of immunoglobulins to neutralize peptides and proteins both before and after they are absorbed. The inevitable result is that the bioavailability of peptides and proteins is likely to be much less than that for small drug molecules, a factor that must be kept in mind in designing realistic strategies to optimize peptide and protein absorption. These strategies include the co-administration of penetration enhancers to alter membrane permeability, coadministration of inhibitors to restrain the activity of proteolytic enzymes primarily at the absorption site, and the design of analogs that are metabolically stable and which, at the same time, may be more readily absorbed.

Keywords

Bile Salt Vasoactive Intestinal Peptide Mixed Micelle Sodium Salicylate Penetration Enhancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anik, S.T., McRae, G., Nerenberg, C., Worden, A., Foreman, J., Hwang, J., Kushinsky, S., Jones, R.E., and Vickery, B., 1984, Nasal absorption of nafarelin in rhesus monkeys, J. Pharm. Sci., 73: 684.PubMedCrossRefGoogle Scholar
  2. Bar-On, H., Berry, E.M., Eldor, A., Kidron, M., Lichtenberg, D., and Ziv, E., 1981, Enterai administration of insulin in the rat, Br. J. Pharmac., 73: 21.CrossRefGoogle Scholar
  3. Bloom, W. and Fawcett, D.W., 1968, “A Textbook of Histology,” W.B. Saunders Co., Philadelphia.Google Scholar
  4. Bocci, V., Naldini, A., Corradeschi, F., and Lencioni, E., 1985, Colorectal administration of human interferon-α, Int. J. Pharm., 24: 109.CrossRefGoogle Scholar
  5. Bocci, V., Pacini, A., Bandinelli, L., Pessina, G.P., Muscettola, M., and Paulesu, L., The role of liver in the catabolism of α-and β-interferon, J. Gen. Virol., 60: 397.Google Scholar
  6. Bunnett, N.W., Orloff, M.S., and Turner, A.J., 1985, Catabolism of substance P in the stomach wall of the rat, Life Sci., 37: 599.PubMedCrossRefGoogle Scholar
  7. Carone, F.A. and Peterson, D.R., 1980, Hydrolysis and transport of small peptides by the proximal tubule, Anu J. Physiol., 238: F151.Google Scholar
  8. Carr, K.E. and Toner, P.G., 1984, Morphology of the intestinal mucosa, in: “Pharmacology of Intestinal Permeation I,” Csaky, T.Z., ed., Springer-Verlag, Berlin.Google Scholar
  9. Cooper, M., Teichberg, S., and Lifshitz, F., 1978, Alterations in rat jejunal permeability to a macromolecular tracer during a hyperosmotic load, Lab. Invest., 38: 447.PubMedCrossRefGoogle Scholar
  10. Dodda Kashi, S. and Lee, V.H.L., 1986, Enkephalin hydrolysis in homogenates of various absorptive mucosae of the albino rabbit: similarities in rates and involvement of aminopeptidases, Life Sci., 38: 2019.CrossRefGoogle Scholar
  11. Gardner, D.F., Kilberg, M.S., Wolfe, M.M., McGuigan, J.E., and Misbin, R.I., 1985, Preferential binding of vasoactive intestinal peptide to hepatic nonparenchymal cells, Am. J. Physiol., 248: G663.PubMedGoogle Scholar
  12. Fix, J.A., Leppert, P.S., Porter, P.A., and Caldwell, L.J., 1983, Influence of ionic strength on rectal absorption of gentamicin sulfate in the presence and absence of sodium salicylate, J. Pharm. Sci., 72: 1134.PubMedCrossRefGoogle Scholar
  13. Hayashi, M., Hirasawa, T., Muraoka, T., Shiga, M., and Awazu, S., 1985, Comparison of water influx and sieving coefficient in rat jejunal, rectal and nasal absorption of antipyrine, Chem. Pharm. Bull., 33: 2149.PubMedCrossRefGoogle Scholar
  14. Hirai, S., Yashiki, T., and Mima, H., 1981a, Effect of surfactants on the nasal absorption of insulin in rats, Int. J. Pharm., 9: 165.CrossRefGoogle Scholar
  15. Hirai, S., Yashiki, T., and Mima, H., 1981b, Mechanisms for the enhancement of the nasal absorption of insulin by surfactants, Int. J. Pharm., 9: 173.CrossRefGoogle Scholar
  16. Hori, R., Komada, F., Okumura, K., 1983, Pharmaceutical approach to subcutaneous dosage forms of insulin, J. Pharm. Sci., 72: 435.PubMedCrossRefGoogle Scholar
  17. Hussain, A., Faraj, J., Aramaki, Y., and Truelove, J.E., 1985, Hydrolysis of leucine enkephalin in the nasal cavity of the rat — a possible factor in the low bioavailability of nasally administered peptides, Biochem. Biophys. Res. Commun.., 133: 923.PubMedCrossRefGoogle Scholar
  18. Ichikawa, K., Ohata, I., Mitomi, M., Kawamura, S., Maeno, H., and Kawata, H., 1980, Rectal absorption of insulin suppositories in rabbits, J. Pharm. Pharmacol., 32: 314.PubMedCrossRefGoogle Scholar
  19. Ishida, M., Machida, Y., Nambu, N., and Nagai, T., 1981, New mucosal dosage form of insulin, Chem. Pharm. Bull., 29, 810–816, 1981.PubMedCrossRefGoogle Scholar
  20. Johnson, V. and Maack, T., 1977, Renal extraction, filtration, absorption, and catabolism of growth hormone, Am. J.Physiol., 233: F185.PubMedGoogle Scholar
  21. Kajii, H., Horie, T., Hayashi, M., and Awazu, S., 1985, Fluorescence study on the interaction of salicylate with rat small intestinal epithelial cells: possible mechanism for the promoting effects of salicylate on drug absorption in vivo, Life Sci., 37: 523.CrossRefGoogle Scholar
  22. Kamada, A., Nishihata, T., Kim, S., Yamamoto, M., and Yata, N., 1981, Study of enamine derivatives of phenylglycine as adjuvants for the rectal absorption of insulin, Chem. Pharm. Bull., 29: 2012.PubMedCrossRefGoogle Scholar
  23. Kidron, M., Bar-On, H., Berry, E.M., and Ziv, E., 1982, The absorption of insulin from various regions of the rat intestine, Life Sci., 31: 2837.PubMedCrossRefGoogle Scholar
  24. Kim, S., Kamada, A., Higuchi, T., and Nishihata, T., 1983, Effect of enamine derivatives on the rectal absorption of insulin in dogs and rabbits, J. Pharm. Pharmacol., 35: 100.PubMedCrossRefGoogle Scholar
  25. Laskowski, M., Haessler, H.A., Miech, R.P., Peanasky, R.J., and Laskowski, M., 1958, Effect of trypsin inhibitor on passage of insulin across the intestinal barrier, Science., 127: 1115.PubMedCrossRefGoogle Scholar
  26. Lee, V.H.L., Carson, L.W., Dodda Kashi, S., and Stratford, R.E., 1986, Barriers to the ocular absorption of topically applied enkephalins, in preparation.Google Scholar
  27. Maack, T., 1975, Renal handling of low molecular weight proteins, Am. J. Med., 58: 57.PubMedCrossRefGoogle Scholar
  28. Martin, G.P., Marriott, C., and Kellaway, I.W., 1978, Direct effect of bile salts and phospholipids on the physical properties of mucus, Gut, 19: 103.PubMedCrossRefGoogle Scholar
  29. Morimoto, K., Kamiya, E., Takeeda, T., Nakamoto, Y., and Morisaka, K., 1983, Enhancement of rectal absorption of insulin in polyacrylic acid aqueous gel bases containing long chain fatty acid in rats, Int. J.Pharm., 14: 149.CrossRefGoogle Scholar
  30. Morimoto, K., Takeeda, T., Nakamoto, Y., and Morisaka, K., 1982, Effective vaginal absorption of insulin in diabetic rats and rabbits using polyacrylic acid aqueous gel bases, Int. J. Pharm., 12: 107.CrossRefGoogle Scholar
  31. Moses, A.C., Gordon, G.S., Carey, M.C., and Flier, J.S., 1983, Insulin administered intranasally as an insulin-bile salt aerosol: effectiveness and reproducibility in normal and diabetic subjects. Diabetes., 32: 1040.PubMedCrossRefGoogle Scholar
  32. Muranishi, S., Tokunaga, Y., Taniguchi, K., and Sezaki, H., 1977, Potential absorption of heparin from the small intestine and the large intestine in the presence of monoolein mixed micelles, Chem. Pharm. Bull., 25: 1159.PubMedCrossRefGoogle Scholar
  33. Muranushi, N., Nakajima, Y., Kinugawa, M., Muranishi, S., Sezaki, H., 1980, Mechanism for the inducement of the intestinal absorption of poorly absorbed drugs by mixed micelles II. Effect of the incorporation of various lipids on the permeability of liposomal membranes. Int. J. Pharm., 4: 281.CrossRefGoogle Scholar
  34. Muranushi, N., Takagi, N., Muranishi, S., and Sezaki, H., 1981, Effect of fatty acids and monoglycerides on permeability of lipid bilayer. Chem. Phys. Lipids, 28: 269.PubMedCrossRefGoogle Scholar
  35. Najdovski, T., Collette, N., and Deschodt-Lanckman, M., 1985, Hydrolysis of the C-terminal octapeptide of cholecystokinin by rat kidney membranes: characterization of the cleavage by solubilized endopeptidase-24.11, Life Sci., 37: 827.PubMedCrossRefGoogle Scholar
  36. Nishihata, T., Higuchi, T., and Kamada, A., 1984a, Salicylate-promoted permeation of cefoxitin, insulin and phenylalanine across red cell membrane. Possible mechanism, Life Sci., 34: 437.PubMedCrossRefGoogle Scholar
  37. Nishihata, T., Kim, S., Morishita, S., Kamada, A., Yata, N., and Higuchi, T., 1983, Adjuvant effects of glyceryl esters of acetoacetic acid on rectal absorption of insulin and inulin in rabbits, J. Pharm. Sci., 72: 280.PubMedCrossRefGoogle Scholar
  38. Nishihata, T., Lee, C.S., Nghiem, B.T., and Higuchi, T., 1984b, Possible mechanism behind the adjuvant action of phosphate derivatives on rectal absorption of cefoxitin in rats and dogs, J. Pharm. Sci., 73: 1523.PubMedCrossRefGoogle Scholar
  39. Nishihata, T., Okamura, Y., Kamada, A., Higuchi, T., Yagi, T., Kawamori, R., and Shichiri, M., 1985a, Enhanced bioavailability of insulin after rectal administration with enamine as adjuvant in depancreatized dogs. J. Pharm. Pharmacol., 37: 22.PubMedCrossRefGoogle Scholar
  40. Nishihata, T., Rytting, J.H., Kamada, A., and Higuchi, T., 1981, Enhanced intestinal absorption of insulin in rats in the presence of sodium 5-methoxysalicylate, Diabetes, 30: 1065.PubMedCrossRefGoogle Scholar
  41. Nishihata, T., Tomida, H., Frederick, G., Rytting, J.H., and Higuchi, T., 1985b, Comparison of the effects of sodium salicylate, disodium ethylenediaminetetraacetic acid and polyoxyethylene-23-lauryl ether as adjuvants for the rectal absorption of sodium cefoxitin, J. Pharm. Sci. 37: 159.Google Scholar
  42. Okada, H., Yamazaki, I., Ogawa, Y., Hirai, S., Yashiki, T., and Mima, H.J., 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.Google Scholar
  43. Okada, H., Yamazaki, I., Ogawa, Y., Hirai, S., Yashiki, T., and Mima, H.J., Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) in rats. II. Mechanism of absorption enhancement with organic acids, J. Pharm. Sci., 72: 75.Google Scholar
  44. Palmieri, F.E., Petrelli, J.J., and Ward, P.E., 1985, Vascular, plasma membrane aminopeptidase M. Metabolism of vasoactive peptides, Biochem. Pharmacol., 34: 2309.PubMedCrossRefGoogle Scholar
  45. Palmieri, F.E. and Ward, P.E., 1983, Mesentery vascular metabolism of substance P, Biochim. Biophys. Acta, 755: 522.PubMedCrossRefGoogle Scholar
  46. Pimstone, B., Epstein, S., Hamilton, S.M., LeRoith, D., and Hendricks, S., Metabolic clearance and plasma half disappearance time of exogenous gonadotropin releasing hormone in normal subjects and in patients with liver disease and chronic renal failure, J. Clin. Endocrinol. Metab., 44: 356.Google Scholar
  47. Pontiroli, A.E., Alberetto, M., Secchi, A., Dossi, G., Bosi, I., and Pozza, G., 1982, Insulin given intranasally induces hypoglycaemia in normal and diabetic subjects, Brit. Med. J., 284: 303.CrossRefGoogle Scholar
  48. Sakai, K., Kutsuna, T.M., Nishino, T., Fujihara, Y., and Yata, N., 1986, Contribution of calcium ion sequestration by polyoxyethylated nonionic surfactants to the enhanced colonie absorption of p-aminoben-zoic acid, J. Pharm. Sci., 75: 387.PubMedCrossRefGoogle Scholar
  49. Segre, G.V., Perkins, A.S., Witters, L.A., and Potts, J.T., Metabolism of parathyroid hormone by isolated rat Kupffer cells and hepatocytes. J. Clin. Invest., 67: 449.Google Scholar
  50. Shiga, M., Muraoka, T., Hirasawa, T., Hayashi, M., and Awazu, S., 1985, The promotion of drug rectal absorption by water absorption, J. Pharm. Pharmacol., 37: 446.PubMedCrossRefGoogle Scholar
  51. Sithigorngul, P., Burton, P., Nishihata, T., and Caldwell, L., 1983, Effects of sodium salicylate on epithelial cells of the rectal mucosa of the rat: a light and electron microscopic study, Life Sci., 33: 1025.PubMedCrossRefGoogle Scholar
  52. Stanzani, L., Mascellani, G., Corbelli, G.P., and Bianchini, P., 1981, Rectal absorption of some glycosaminoglycan sulphates and heparin in rats, J. Pharm. Pharmacol., 33: 783.PubMedCrossRefGoogle Scholar
  53. 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.CrossRefGoogle Scholar
  54. Strunz, U.T., Thompson, M.R., Elashoff, J., and Grossman, M.I., 1978, Hepatic inactivation of gastrins of various chain lengths in dogs, Gastroenterology, 74: 550.PubMedGoogle Scholar
  55. Su, K.S.E., Campanale, K.M., Mendelsohn, L.G., Kerchner, G.A., and Gries, C.L., 1985, Nasal delivery of polypeptides I: Nasal absorption of enkephalins in rats, J. Pharm. Sci., 74: 394.PubMedCrossRefGoogle Scholar
  56. Taniguchi, K., Muranishi, S., and Sezaki, H., 1980, Enhanced intestinal permeability to macromolecules II. Improvment of the large intestinal absorption of heparin by lipid-surfactant mixed micelles in rat. Int. J. Pharm., 4: 219.CrossRefGoogle Scholar
  57. Temperley, J.M., Stagg, B.H., and Wyllie, J.H., 1971, Disappearance of gastrin and pentagastrin in the portal circulation, Gut, 12: 372.PubMedCrossRefGoogle Scholar
  58. Touitou, E., Donbrow, M., and Azaz, E., 1978, New hydrophilic vehicle enabling rectal and vaginal absorption of insulin, heparin, phenol red, and gentamicin, J. Pharm. Pharmacol., 30: 662.PubMedCrossRefGoogle Scholar
  59. Touitou, E., Donbrow, M., and Rubinstein, A., 1980, Effective intestinal absorption of insulin in diabetic rats using a new formulation approach, J. Pharm. Pharmacol., 32: 108.PubMedCrossRefGoogle Scholar
  60. Ward, P.E., 1984, Immunoelectrophoretic analysis of vascular, membrane-bound angiotensin I converting enzyme, aminopeptidase M, and dipep-tidyl(amino)peptidase IV, Biochem. Pharmacol., 33: 3183.PubMedCrossRefGoogle Scholar
  61. Yagi, T., Hakui, N., Yamasaki, Y., Kawamori, R., Shichiri, M., Abe, H., Kim, S., Miyake, M., Kamikawa, K., Nishihata, T., and Kamada, A., Insulin suppository: enhanced rectal absorption of insulin using an enamine derivative as a new promoter, J. Pharm. Pharmacol., 35: 177.Google Scholar
  62. Yamashita, S., Saitoh, H., Nakanishi, K., Masada, M., Nadai, T., and Kimura, T., 1985, Characterization of enhanced intestinal permeability; electrophysiological study on the effects of diclofenac and ethylenediaminetetraacetic acid, J. Pharm. Pharmacol., 37: 512.PubMedCrossRefGoogle Scholar
  63. Yoshioka, S., Caldwell, L., and Higuchi, T., 1982, Enhanced rectal bioavailability of polypeptides using sodium 5-methoxysalicylate as an absorption promoter, J. Pharm. Sci., 71: 593.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1986

Authors and Affiliations

  • Vincent H. L. Lee
    • 1
  1. 1.School of PharmacyUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations