Skip to main content
Log in

Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit, Monkey, and Dog Intestine and Human Drug Absorption

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

The in vitro permeabilities of Caco-2 monolayers and permeabilities in tissue sections from colon of monkey, rabbit, and dog were compared using a series of compounds. The selected compounds differed in their physicochemical properties, such as octanol/water partition coefficient, water solubility, and molecular weight. Their structure included steroids, carboxylic acids, xanthins, alcohols, and polyethylene glycols. A linear permeability relationship was established between Caco-2 and colon tissue from both rabbit and monkey. The results suggest that Caco-2 is twice as permeable as rabbit and five times as permeable as monkey colon. However, no clear relationship could be established between Caco-2 monolayers and dog colon permeability. A relationship between permeability in Caco-2 monolayers and human absorption was found. The results suggest that within certain limits, permeability of Caco-2 monolayers may be used as a predictive tool to estimate human drug absorption.

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

Access this article

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

  1. G. M. Grass and St. Sweetana. In vitro measurement of gastrointestinal tissue permeability using a new diffusion cell. Pharm. Res. 5:372–376 (1988).

    Google Scholar 

  2. G. M. Grass and S. A. Sweetana. A correlation of permeabilities for passively transported compounds in monkey and rabbit jejunum. Pharm. Res. 6:857–862 (1989).

    Google Scholar 

  3. K. L. Audus, R. L. Bartel, I. Hidalgo, and R. T. Borchardt. The use of cultured epithelial and endothelial cells for drug transport and metabolism studies. Pharm. Res. 7:435–451 (1990).

    Google Scholar 

  4. P. Artursson. Epithelial transport of drugs in cell culture. I. A model for studying the passive diffusion of drugs over intestinal absorption (Caco-2) cells. J. Pharm. Sci. 79:476–482 (1990).

    Google Scholar 

  5. P. Artursson and Ch. Magnusson. Epithelial transport of drugs in cell culture. II. Effect of extracellular calcium concentration on the paracellular transport of different lipophilicities across monolayers of intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 79:595–600 (1990).

    Google Scholar 

  6. P. Artursson and J. Karlsson. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Comm. 175:880–885 (1991).

    Google Scholar 

  7. N. Jezyk, W. Rubas, and G. M. Grass. Permeability characteristics of various intestinal regions of rabbit, dog, and monkey (submitted for publication). Pharm. Res. 9:1580–1586 (1992).

    Google Scholar 

  8. I. J. Hidalgo, K. M. Hillgren, G. M. Grass, and R. T. Borchardt. Characterization of the unstirred water layer in Caco-2 cell monolayers using a novel diffusion apparatus. Pharm. Res. 8:222–227 (1991).

    Google Scholar 

  9. I. J. Hidalgo, T. J. Raub, and R. T. Borchardt. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96:736–749 (1989).

    CAS  PubMed  Google Scholar 

  10. D. Hollander, D. Ricketts, and C. A. R. Boyd. Importance of “probe” molecular geometry in determining intestinal permeability. Can. J. Gastroenterol. 2 (Suppl. A):35A–38A (1988).

    Google Scholar 

  11. V. S. Chadwick, S. F. Phillips, and A. F. Hofmann. Measurements of intestinal permeability using low molecular weight polyethylenglycols (PEG 400). Gastroenterology 73:241–246 (1977).

    Google Scholar 

  12. D. G. Maxton, I. Bjarnason, A. P. Reynolds, D. Catt, T. J. Peters, and I. S. Menzies. 51Cr-Labeled ethylendiaminetetraacetate, L-rhamnose and polyethylenglycol 500 as probe markers for assessment in vivo of human intestinal permeability. Clin. Sci. 71:71–80 (1986).

    Google Scholar 

  13. K. Faith-Magnusson, N. I. M. Kjellman, K. E. Magnusson, and T. Sundquist. Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized polyethylenglycols (PEG 400 and PEG 1000). Clin. Allergy 14:277–286 (1984).

    Google Scholar 

  14. C. Tagesson and R. Sjodahl. Passage of the molecules through the wall of the gastrointestinal tract. Urinary recovery of different-sized polyethylenglycols after intravenous and intestinal deposition. Scand. J. Gastroenterol. 19:315–320 (1984).

    Google Scholar 

  15. K. Faith-Magnusson, N. I. M. Kjellman, K. E. Magnusson, and T. Sundquist. Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized polyethylenglycols (PEG 400 and PEG 1000). Clin. Allergy 14:277–286 (1984).

    Google Scholar 

  16. C. Tagesson and R. Sjodahl. Passage of the molecules through the wall of the gastrointestinal tract. Urinary recovery of different-sized polyethylenglycols after intravenous and intestinal deposition. Scand. J. Gastroenterol. 19:315–320 (1984).

    Google Scholar 

  17. E. F. Phillipsen, W. Batsberg, and A. B. Christensen. Gastrointestinal permeability to polyethylenglycol: An evaluation of urinary recovery of an oral load of polyethylenglycol as a parameter of intestinal permeability in man. Eur. J. Clin. Invest. 18:139–145 (1988).

    Google Scholar 

  18. N. F. H. Ho, J. Y. Park, W. Morozowich, and W. I. Higuchi. Physical model approach to the design of drugs with improved intestinal absorption. In E. B. Roche (ed.), Design of Biopharmaceutical Properties Through Prodrugs and Analogs, American Pharmaceutical Association, Academy of Pharmaceutical Sciences, Washington, D.C., 1977, pp. 136–227.

    Google Scholar 

  19. S. H. Yalkowsky and W. Morozowich. A physical chemical basis of the design of orally active prodrugs. Drug Design 9:122–185 (1980).

    Google Scholar 

  20. M. J. Jackson. Drug transport across gastrointestinal epithelia. In L. R. Johnson (ed.), Physiology of the Gastrointestinal Tract, 2nd ed., Raven Press, New York, 1987, pp. 1597–1621.

    Google Scholar 

  21. S. S. Davis, T. Higuchi, and J. H. Rytting. Determination of thermodynamics of the methylene group in solutions of drug molecules. J. Pharm. Pharmacol. (Suppl.) 24:30–46 (1974).

    Google Scholar 

  22. I. Komiya, J. Y. Park, N. F. Ho, and W. I. Higuchi. Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes. Int. J. Pharm. 4:249–262 (1980).

    Google Scholar 

  23. N. W. Read, D. C. Barber, R. J. Levin, and C. D. Holdsworth. Unstirred layer and kinetics of electrogenic glucose absorption in the human jejunum in situ. Gut 18:865–876 (1977).

    Google Scholar 

  24. F. A. Wilson and J. M. Dietschy. The intestinal unstirred layer: Its surface area and effect on active transport kinetics. Biochim. Biophys. Acta 363:112–126 (1974).

    Google Scholar 

  25. J. R. Pappenheimer. Paracellular intestinal absorption of glucose, creatinine, and mannitol in normal animals: Relation to body size. Am. J. Physiol. 259:G290–G299 (1990).

    Google Scholar 

  26. J. B. Meddings and H. Westergaard. Intestinal glucose transport using perfused rat jejunum in vivo: Model analysis and derivation of kinetic constants. Clin. Sci. 76:403–413 (1989).

    Google Scholar 

  27. M. P. Vinardelli and J. Bolufer. Paracellular absorption of D-glucose by rat small intestine in vivo. Rev. Esp. Fisiol. 39:193–196 (1983).

    Google Scholar 

  28. S. A. Riley, G. Warhust, P. T. Crowe, and L. A. Turnberg. Active hexose transport across cultured human Caco-2 cells: characterization and influence of culture conditions. Biochim. Biophys. Acta 1066:175–182 (1991).

    Google Scholar 

  29. I. Cobden, J. Rothwell, and A. T. R. Axon. Intestinal permeability and screening tests for celiac disease. Gut 21:512–518 (1980).

    Google Scholar 

  30. M. V. Calvo, A. Dominguez-Gil, J. M. Miralles, and F. DePablo. Pharmakokinetic of naproxen in healthy-volunteers and patients with diabetic microangiopathy. Int. J. Clin. Pharm. Biopharm. 17:486–491 (1979).

    Google Scholar 

  31. S. O. Ukabam and B. T. Cooper. Small intestinal permeability to mannitol, lactulose, and polyethylene glycol 400 in celiac diseases. Digest. Dis. Sci. 29:809–816 (1984).

    Google Scholar 

  32. F. Andre, C. Andre, Y. Emery, J. Forichon, L. Descos, and Y. Minaire. Assessment of the lactulose-mannitol test in Crohn's disease. Gut 29:511–515 (1988).

    Google Scholar 

  33. R. Runkel, E. Forchielli, H. Sevelius, M. Chaplin, and E. Segre. Nonlinear plasma level response to high doses of naproxen. Clin. Pharmacol. Ther. 15:261–266 (1973).

    Google Scholar 

  34. R. E. Peterson, J. B. Wyngaarden, S. L. Guerra, B. B. Brodie, and J. J. Bunim. The physiological disposition and metabolic fate of hydrocortisone in man. J. Clin. Invest. 34:1779–1794 (1955).

    Google Scholar 

  35. H. P. Schedl. Absorption of steroid hormones from the human small intestine. J. Clin. Endocrinol. Metab. 25:1309–1316 (1965).

    Google Scholar 

  36. M. D. Donovan, G. L. Flynn, and G. L. Amidon. Absorption of polyethylene glycols 600 through 2000: The molecular weight dependence of gastrointestinal and nasal absorption. Pharm. Res. 7:863–867 (1990).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rubas, W., Jezyk, N. & Grass, G.M. Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit, Monkey, and Dog Intestine and Human Drug Absorption. Pharm Res 10, 113–118 (1993). https://doi.org/10.1023/A:1018937416447

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018937416447

Navigation