Skip to main content
SpringerLink
Log in

Transepithelial Transport of Diphenhydramine Across Monolayers of the Human Intestinal Epithelial Cell Line Caco-2

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. The transepithelial transport characteristics of theantihistamine, diphenhydramine, were studied in human intestinal Caco-2 cellmonolayers to elucidate the mechanisms of its intestinal absorption.

Methods. The transepithelial transport and the cellular accumulationof diphenhydramine were measured using Caco-2 cell monolayersgrown in Transwell chambers.

Results. The transepithelial transport of diphenhydramine from theapical to basolateral side was saturable, and the flux and cellularaccumulation of diphenhydramine were dependent on the apicalextracellular pH (pH 7.4 > 6.5 > 5.5). Transport and accumulation ofdiphenhydramine from the apical side were inhibited by anotherantihistamine, chlorpheniramine, while typical substrates for the renal organiccation transport system such as tetraethylammonium, cimetidine andguanidine had no effect. The transepithelial transport and cellularaccumulation of diphenhydramine from the basolateral side were alsopH-dependent and inhibited by chlorpheniramine. In addition, intracellulardiphenhydramine preloaded was preferentially effluxed to the apicalside, suggesting the involvement of the secretory pathway indiphenhydramine transport. Furthermore, diphenhydramine uptake from boththe apical and basolateral sides was stimulated by preloadingmonolayers with chlorpheniramine (trans-stimulation effect).

Conclusions. Transepithelial transport of diphenhydramine acrossCaco-2 cells is mediated by pH-dependent, specific transport systemsthat exist in both the apical and basolateral membranes.

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.

Similar content being viewed by others

REFERENCES

  1. T. Tan, M. Kuramoto, T. Takahashi, H. Nakamura, Y. Nakanishi, Y. Imasato, and H. Yoshimura. Characteristics of the gastrointestinal absorption of morphine in rats. Chem. Pharm. Bull. 37:168–173 (1989).

    Google Scholar 

  2. S. M. Kuo, B. R. Whitby, P. Artursson, and J. A. Ziemniak. The contribution of intestinal secretion to the dose-dependent absorption of celiprolol. Pharm. Res. 11:648–653 (1994).

    Google Scholar 

  3. I. Tamai, A. Saheki, R. Saitoh, Y. Sai, I. Yamada, and A. Tsuji. Nonlinear intestinal absorption of 5-hydroxytryptamine receptor antagonist caused by absorptive and secretory transporters. J. Pharmacol. Exp. Ther. 283:108–115 (1997).

    Google Scholar 

  4. H. Lennernäs and C.-G. Regå rdh. Dose-dependent intestinal absorption and significant intestinal excretion (exsorption) of the β-blocker pafenolol in the rat. Pharm. Res. 10:727–731 (1993).

    Google Scholar 

  5. T. Koudriakova, E. Iatsimirskaia, S. Tulebaev, D. Spetie, I. Utkin, D. Mullet, T. Thompson, P. Vouros, and N. Gerber. In vivo disposition and metabolism by liver and enterocyte microsomes of the antitubercular drug rifabutin in rats. J. Pharmacol. Exp. Ther. 279:1300–1309 (1996).

    Google Scholar 

  6. T. Gramatté, R. Oertel, B. Terhaag, and W. Kirch. Direct demonstration of small intestinal secretion and site-dependent absorption of the β-blocker talinolol in humans. Clin. Pharmacol. Ther. 59:541–549 (1996).

    Google Scholar 

  7. K. Turnheim and F. O. Lauterbach. Absorption and secretion of monoquaternary ammonium compounds by the isolated intestinal mucosa. Biochem. Pharmacol. 26:99–108 (1977).

    Google Scholar 

  8. K. Turnheim and F. Lauterbach. Interaction between intestinal absorption and secretion of monoquaternary ammonium compounds in guinea pigs· a concept for the absorption kinetics of organic cations. J. Pharmacol. Exp. Ther. 212:418–424 (1980).

    Google Scholar 

  9. Y. Miyamoto, V. Ganapathy, and F. H. Leibach. Transport of guanidine in rabbit intestinal brush-border membrane vesicles. Am. J. Physiol. 255:G85–G92 (1988).

    Google Scholar 

  10. S. Hsing, Z. Gatmaitan, and I. M. Arias. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 102:879–885 (1992).

    Google Scholar 

  11. H. Koepsell. Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol. 60:243–266 (1998).

    Google Scholar 

  12. L. Zhang, C. M. Brett, and K. M. Giacomini. Role of organic cation transporters in drug absorption and elimination. Annu. Rev. Pharmacol. Toxicol. 38:431–460 (1998).

    Google Scholar 

  13. P. Artursson and R. T. Borchardt. Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharm. Res. 14:1655–1658 (1997).

    Google Scholar 

  14. 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).

    Google Scholar 

  15. K. Inui, M. Yamamoto, and H. Saito. Transepithelial transport of oral cephalosporins by monolayers of intestinal epithelial cell line Caco-2: specific transport systems in apical and basolateral membranes. J. Pharmacol. Exp. Ther. 261:195–201 (1992).

    Google Scholar 

  16. H. Saito and K. Inui. Dipeptide transporters in apical and basolateral membranes of the human intestinal cell line Caco-2. Am. J. Physiol. 265:G289¶ G294 (1993).

    Google Scholar 

  17. S. Matsumoto, H. Saito, and K. Inui. Transcellular transport of cephalosporins in human intestinal epithelial cells, Caco-2: interaction with dipeptide transport systems in apical and basolateral membranes. J. Pharmacol. Exp. Ther. 270:498–504 (1994).

    Google Scholar 

  18. H. Mizuuchi, T. Katsura, H. Saito, Y. Hashimoto, and K. Inui. Transport characteristics of diphenhydramine in human intestinal epithelial Caco-2 cells: contribution of pH-dependent transport system. J. Pharmacol. Exp. Ther. 290:388–392 (1999).

    Google Scholar 

  19. D. M. Paton and D. R. Webster. Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin. Pharmacokinet. 10:477–497 (1985).

    Google Scholar 

  20. A. M. de Roos, R. F. Rekker, and W. T. Nauta. The base strength of substituted 2-(diphenylmethoxy)-N,N-dimethylethylamines. Arzneim. Forsch. 20:1763–1765 (1970).

    Google Scholar 

  21. H. Saitoh and B. J. Aungst. Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine. Pharm. Res. 12:1304–1310 (1995).

    Google Scholar 

  22. K. Arimori and M. Nakano. Drug exsorption from blood into the gastrointestinal tract. Pharm. Res. 15:371–376 (1998).

    Google Scholar 

  23. F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA 84:7735–7738 (1987).

    Google Scholar 

  24. J. Hunter, M. A. Jepson, T. Tsuruo, N. L. Simmons, and B. H. Hirst. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interaction with modulators. J. Biol. Chem. 268:14991–14997 (1993).

    Google Scholar 

  25. J. Hunter, B. H. Hirst, and N. L. Simmons. Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers. Pharm. Res. 10:743–749 (1993).

    Google Scholar 

  26. J. Karlsson, S.-M. Kuo, J. Ziemniak, and P. Artursson. Transport of celiprolol across human intestinal epithelial (Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein. Br. J. Pharmacol. 110:1009–1016 (1993).

    Google Scholar 

  27. T. Ito, I. Yano, K. Tanaka, and K. Inui. Transport of quinolone antibacterial drugs by human P-glycoprotein expressed in a kidney epithelial cell line, LLC-PK1. J. Pharmacol. Exp. Ther. 282:955–960 (1997).

    Google Scholar 

  28. K. Tanaka, M. Hirai, Y. Tanigawara, K. Ueda, M. Takano, R. Hori, and K. Inui. Relationship between expression level of P-glycoprotein and daunorubicin transport in LLC-PK1 cells transfected with human MDR1 gene. Biochem. Pharmacol. 53:741–746 (1997).

    Google Scholar 

  29. K. Inui and M. Okuda. Cellular and molecular mechanisms of renal tubular secretion of organic anions and cations. Clin. Exp. Nephrol. 2:100–108 (1998).

    Google Scholar 

  30. U. Laforenza, M. N. Orsenigo, and G. Rindi. A thiamine/H+ antiport mechanism for thiamine entry into brush border membrane vesicles from rat small intestine. J. Membr. Biol. 161:151–161 (1998).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, Kyoto University Hospital, Japan

    Hiroshi Mizuuchi, Toshiya Katsura, Yukiya Hashimoto & Ken-ichi Inui

  2. Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Hiroshi Mizuuchi, Toshiya Katsura & Yukiya Hashimoto

  3. Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Ken-ichi Inui

Authors
  1. Hiroshi Mizuuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiya Katsura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yukiya Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ken-ichi Inui
    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

Mizuuchi, H., Katsura, T., Hashimoto, Y. et al. Transepithelial Transport of Diphenhydramine Across Monolayers of the Human Intestinal Epithelial Cell Line Caco-2. Pharm Res 17, 539–545 (2000). https://doi.org/10.1023/A:1007560731098

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007560731098

Search

Navigation