Abstract
The effects of the absorption enhancer sodium caprate on human intestinal epithelial cells were investigated using Caco-2 cell monolayers. The effects on epithelial integrity and drug transport are dependent on time and concentration and are decreased by Ca2+, most likely through the formation of Ca22+ soaps. Morphological data indicate that exposure to sodium caprate results in cytoskeletal changes and in structural alterations of the tight junctions in the form of dilatations, while the effects on the apical cell membranes are limited. We conclude that sodium caprate increases the absorption of drugs mainly by the paracellular route.
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REFERENCES
A. Helenius and K. Simons. Solubilization of membranes by detergents. Biochim. Biophys. Acta 415:29–79 (1975).
T. Y. Ma, D. Hollander, R. A. Erickson, H. Truong, and P. Krugliak. Is the small intestinal epithelium truly ‘tight’ to inulin permeation. Am. J. Physiol. 260:G669–G676 (1991).
J. R. Pappenheimer. Physiological regulation of transepithelial impedance in the intestinal mucosa of rats and hamsters. J. Membr. Biol. 100:137–148 (1987).
V. H. L. Lee. Enzymatic barriers to peptide and protein absorption and the use of penetration enhancers to modify absorption. In Proceedings, NATO Advanced Research Workshop on Advanced Drug Delivery Systems for Peptides and Proteins, Copenhangen, Denmark, Plenum Press, New York, 1986, pp. 87–104.
E. J. van Hoogdalem, A. G. de Boer, and D. D. Breimer. Intestinal drug absorption enhancement, an overview. Pharmacol. Ther. 44:407–443 (1989).
V. H. L. Lee and A. Yamamoto. Penetration and enzymatic barriers to peptide and protein absorption. Adv. Drug Deliv. Rev. 4:171–207 (1990).
E. K. Anderberg and P. Artursson. Epithelial transport of drugs in cell culture. VIII. The effects of the pharmaceutical surfactant excipient sodium dodecyl sulfate on cell membrane and tight junction permeability in human intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 82:392–398 (1993).
T. Murakami, H. Kawakita, M. Kishimoto, Y. Higashi, H. Amagase, T. Hayashi, N. Nojima, T. Fuwa, and N. Yata. Intravenous and subcutaneous pharmacokinetics and rectal bioavailability of human epidermal growth factor in the presence of absorption promoter in rats. Int. J. Pharm. 46:9–17 (1988).
M. Tomita, M. Shiga, M. Hayashi, and S. Awazu. Enhancement of colonic drug absorption by the paracellular permeation route. Pharm. Res. 5:341–346 (1988).
M. Tomita, M. Hayashi, T. Horie, T. Ishizawa, and S. Awazu. Enhancement of colonic drug absorption by the transcellular permeation route. Pharm. Res. 5:786–789 (1988).
T. Sawada, T. Ogawa, M. Tomita, M. Hayashi, and S. Awazu. Role of paracellular pathway in nonelectrolyte permeation across rat colon epithelium enhanced by sodium caprate and sodium caprylate. Pharm. Res. 8:1365–1371 (1991).
E. K. Anderberg, C. Nyström, and P. Artursson. Epithelial transport of drugs in cell culture. VII. Effects of pharmaceutical surfactant excipients and bile acids on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 81:879–887 (1992).
I. Chantret, A. Barbat, E. Dussalaux, M. G. Brattain, and A. Zweibaum. Epithelial polarity, villin expression, and enterocytic differentation of human colon carcinoma cells: A survey of twenty cell lines. Cancer Res. 48:1936–1942 (1988).
P. Artursson. Epithelial transport of drugs in cell culture. I. A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J. Pharm. Sci. 79:476–482 (1990).
P. Artursson and C. Magnusson. Epithelial transport of drugs in cell culture. II. Effect of extracellular calcium concentration on the paracellular transport of drugs of different lipophilicities across monolayers of intestinal epithelial (Caco-2) cells. J. Pharm. Sci. 79:595–600 (1990).
K. H. Jones and J. A. Senft. An improved method to determine cell viability by simultaneous staining with fluorescein diacetate-propidium iodide. J. Histochem. Cytochem. 33:77–79 (1985).
M. J. Wargovich, V. W. S. Eng, and H. L. Newmark. Calcium inhibits the damaging and compensatory proliferative effects of fatty acids on mouse colon epithelium. Cancer Lett. 23:253–258 (1984).
M. Mishima, Y. Wakita, and M. Nakano. Studies on the promoting effects of medium chain fatty acid salts on the nasal absorption of insulin in rats. J. Pharmacobio-Dyn. 10:624–631 (1987).
M. J. Wargovich, W. S. Eng, H. L. Newmark, and W. R. Bruce. Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis 4:1205–1207 (1983).
J. J. Rafter, V. W. S. Eng, R. Furrer, A. Medline, and W. R. Bruce. Effects of calcium and pH on the mucosal damage produced by deoxycholic acid in the rat colon. Gut 27:1320–1329 (1986).
N. Yata, Y. Higashi, T. Murakami, R. Yamajo, W. M. Wu, K. Taku, Y. Sasaki, and Y. Hideshima. A possible mechanism of absorption promoters. J. Pharm. Dyn. 6:78 (1983).
N. Kakeya. Antibiotic suppositories. In Proceedings of a Workshop Held at the 14th International Conference of Chemotherapy, University of Tokyo Press, Tokyo, 1985, pp. 15–22.
K.-I. Nishimura, Y. Nozaki, A. Yoshimi, S. Nakamura, M. Kitagawa, N. Kakeya, and K. Kitao. Studies on the promoting effects of carboxylic acid derivatives on the rectal absorption of β-lactam antibiotics in rats. Chem. Pharm. Bull. 33:282–291 (1985).
B. Gumbiner. Structure, biochemistry and assembly of epithelial tight junctions. Am. J. Physiol. 253:C749–C758 (1987).
J. L. Madara, D. Barenberg, and S. Carlson. Effects of cytochalasin D on occluding junctions of intestinal absorptive cell: Further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J. Cell Biol. 102:2125–2136 (1986).
G. Hecht, J. Pothoulakis, J. T. LaMont, and J. L. Madara. Clostridium difficile Toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J. Clin. Invest. 82:1516–1524 (1988).
J. L. Madara, J. Stafford, D. Barenberg, and S. Carlson. Functional coupling of tight junctions and microfilaments in T84 monolayers. Am. J. Physiol. 254:G416–G423 (1988).
J. Llopis, G. E. N. Kass, S. K. Duddy, G. C. Farrel, A. Gahm, and S. Orrenius. Mobilization of the hormone-sensitive calcium pool increases hepatocyte tight junctional permeability in the perfused rat liver. FEBS Lett. 280:84–86 (1991).
K. Atisook, S. Carlson, and J. L. Madara. Effects of phlorizin and sodium on glucose-elicited alterations of cell junctions in intestinal epithelia. Am. J. Physiol. 258:C77–C85 (1990).
M. Shiga, M. Hayashi, T. Horie, and S. Awazu. Promotion of drug rectal absorption related to water absorption. Chem. Pharm. Bull. 34:2254–2256 (1986).
P. R. Kvietys, R. D. Specian, M. B. Grisham, and P. Tso. Jejunal mucosal injury and restitution: Role of hydrolytic products of food digestion. Am. J. Physiol. 261:G384–G391 (1991).
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Anderberg, E.K., Lindmark, T. & Artursson, P. Sodium Caprate Elicits Dilatations in Human Intestinal Tight Junctions and Enhances Drug Absorption by the Paracellular Route. Pharm Res 10, 857–864 (1993). https://doi.org/10.1023/A:1018909210879
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DOI: https://doi.org/10.1023/A:1018909210879