Pharmaceutical Research

, Volume 14, Issue 9, pp 1210–1215 | Cite as

Estimation of the Relative Contribution of the Transcellular and Paracellular Pathway to the Transport of Passively Absorbed Drugs in the Caco-2 Cell Culture Model



Purpose. The objective of this investigation was to determine, using the Caco-2 cell culture model, the extent to which the paracellular and transcellular routes contributed to the transport of passively absorbed drugs. An effort was also made to determine the controlling factors in this process.

Methods. We selected a heterologous series of drugs with varying physicochemical parameters for the investigation. Effective permeability coefficients of the model drugs (naproxen, phenytoin, salicylic acid, chlorothiazide, furosemide, propranolol, diltiazem, ephedrine, and cimetidine), at pH 7.2 and pH 5.4, were estimated using confluent monolayers of Caco-2 cells. The biophysical model approach, based on molecular size restricted diffusion within an electrostatic field of force, used by Adson et al. (1 ,2), was employed to estimate the permeability coefficients of the ionized and unionized forms of the drugs for the paracellular and transcellular route.

Results and Conclusions. The permeability coefficients of the acidic drugs was greater at pH 5.4, whereas that of the basic drugs was greater at pH 7.2 and the transcellular pathway was the favored pathway for most drugs, probably due to its larger accessible surface area. The paracellular permeability of the drugs was size and charge dependent. The permeability of the drugs through the tight junctions decreased with increasing molecular size. Further, the pathway also appeared to be cation-selective, with the positively charged cations of weak bases permeating the aqueous pores of the paracellular pathway at a faster rate than the negatively charged anions of weak acids. Thus, the extent to which the paracellular and transcellular routes are utilized in drug transport is influenced by the fraction of ionized and unionized species (which in turn depends upon the pKa of the drug and the pH of the solution), the intrinsic partition coefficient of the drug, the size of the molecule and its charge.

permeability paracellular transcellular transport, Caco-2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A. Adson, T. J. Raub, P. S. Burton, C. L. Barsuhn, A. R. Hilgers, K. L. Audus, and N. F. H. Ho. J. Pharm. Sci. 83:1529–1536 (1994).Google Scholar
  2. 2.
    A. Adson, P. S. Burton, T. J. Raub, C. L. Barsuhn, K. L. Audus, and N. F. H. Ho. J. Pharm. Sci. 84:1197–1204 (1995).Google Scholar
  3. 3.
    A. R. Hilgers, R. A. Conradi, and P. S. Burton. Pharm. Res. 7:902–910 (1990).Google Scholar
  4. 4.
    G. Wilson, I. F. Hassan, C. J. Dix, I. Williamson, R. Shah, and M. Mackay. J. Controlled Release 11:25–40 (1990).Google Scholar
  5. 5.
    P. Artursson. J. Pharm. Sci. 79:476–482 (1990).Google Scholar
  6. 6.
    J. N. Cogburn, M. Donovan, and C. Schasteen. Pharm. Res. 8:210–216 (1991).Google Scholar
  7. 7.
    I. J. Hidalgo, T. J. Raub, and R. T. Borchardt. Gastroenterology 96:736–749 (1989).Google Scholar
  8. 8.
    M. Rousset. Biochimie 68:1035–1040 (1986).Google Scholar
  9. 9.
    M. Pinto, S. Leon-Robine, M. D. Appay, M. Kedinger, N. Triadou, E. Dussaulx, B. Lacroix, P. Assmann-Simon, K. Haffen, J. Fogh, and A. Zweibaum. Biol. Cell. 47:323–330 (1983).Google Scholar
  10. 10.
    T. Teorell. Prog. Biophys. Mol. Biol. 3:305–369 (1953).Google Scholar
  11. 11.
    R. S. Pearlman. Molecular Surface Area and Volume. In: W. J. Dunn, J. H. Block, R. S. Pearlman, editors. Partition Coefficient. Determination and Estimation. New York: Pergamon Press, 1986:3–20.Google Scholar
  12. 12.
    E. L. Cussler. Diffusion: Mass Transfer in Fluid Systems, Cambridge University Press, NY (1986).Google Scholar
  13. 13.
    E. M. Renkin. J. Gen. Physiol. 38:225–243 (1955).Google Scholar
  14. 14.
    F. E. Curry. Mechanisms and thermodynamics of transcapillary exchange. In: E. M. Renkin, C. C. Michel, editors. The Cardiovascular System. Vol. IV. Microcirculation. Part 1. Bethesda, MD: Am. Physiol. Society, 1977:309–374.Google Scholar
  15. 15.
    P. A. Shore, B. B. Brodie, and C. A. M. Hogben. J. Pharmacol. Exp. Ther. 119:361–369 (1957).Google Scholar
  16. 16.
    J. L. Madara and K. Dharmsathaphorn. J. Cell Biol. 101:2124–2133 (1985).Google Scholar
  17. 17.
    K. H. Soergel Gastroenterology 105:1247–1250 (1993).Google Scholar
  18. 18.
    N. F. H. Ho, D. P. Thompson, T. G. Geary, T. J. Raub, and C. L. Barsuhn. Molec. Biochem. Parasitol. 41:153–166 (1990).Google Scholar
  19. 19.
    S. T. Ballard, J. H. Hunter, and A. E. Taylor. Annu. Rev. Nutr. 15:35–55 (1995).Google Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  1. 1.Pharmaceutics Division, College of PharmacyThe University of Texas at AustinAustin

Personalised recommendations