Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Enhancement of Heparin and Heparin Disaccharide Absorption by the Phytolacca americana Saponins

  • Cho, So-Yean (Natural Products Research Institute, College of Pharmacy Seoul National University) ;
  • Sim, Joon-Soo (Natural Products Research Institute, College of Pharmacy Seoul National University) ;
  • Kang, Sam-Sik (Natural Products Research Institute, College of Pharmacy Seoul National University) ;
  • Jeong, Choon-Sik (College of Pharmacy, Duksung Women's University) ;
  • Linhardt, Robert-J (Department of Chemistry, Biology and Chemical Biological Engineering, Rensselaer Polytechnic Institute) ;
  • Kim, Yeong-Shik (Natural Products Research Institute, College of Pharmacy Seoul National University)
  • Published : 2003.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

We studied the effects of phytolaccosides, saponins from Phytolacca americana, on the intestinal absorption of heparin in vitro and in vivo. The absorption enhancing activity of these compounds (phytolaccosides B, $D_2$, E, F, G and I) was determined by changes in transepithelial electrical resistance (TEER) and the transport amount of heparin disaccharide, the major repeating unit of heparin, across Caco-2 cell monolayers. With the exception of phytolaccoside G, all of them decreased TEER values and increased the permeability in a dose-dependent and time-dependent manner. In vitro, phytolaccosides B,$D_2$, and E showed significant absorption enhancing activities, while effects by phytolaccoside F and I were mild. In vivo, phytolaccoside E increased the activated partial thromboplastin time (APTT) and thrombin time, indicating that phytolaccoside E modulated the transport of heparin in intestinal route. Our results suggest that a series of phytolaccosides from Phytolacca americana can be applied as pharmaceutical excipients to improve the permeability of macromolecules and hydrophilic drugs having difficulty in absorption across the intestinal epithelium.

Keywords

References

  1. Anderson, J. M. and van Itallie, C. M., Tight junctions and the molecular basis for regulation of paracellular permeability. Am. J. Physiol., 269, 467-475 (1995)
  2. Baughman, R. A., Kapoor, S. C., Agarwal, R. K., Kisicki, J., Catella-Lawson, F., and FitzGerald, G. A., Oral delivery of anticoagulant doses of heparin. A randomized, double- blind, controlled study in humans. Circulation, 98, 1610-1615 (1998) https://doi.org/10.1161/01.CIR.98.16.1610
  3. Brayden, D., Creed, E., O'Connell, A., Leipold, H., Agarwal, R., and Leone-Bay, A., Heparin absorption across the intestine: effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate in rat in situ intestinal instillations and in Caco-2 monolayers. Pharm. Res., 14, 1772-1779 (1997) https://doi.org/10.1023/A:1012192115828
  4. Caramazza, I., D'Atri, G., Bossi, M. L., De Ponti, F., D'Angelo, L., and Crema, A., Intraduodenal absorption of the new UF-heparin salt ITF 1057 in the conscious dog. Thromb. Res., 62, 785-789 (1991) https://doi.org/10.1016/0049-3848(91)90383-8
  5. Chao, A. C., Nguyen, J. V., Broughall, M., Recchia, J., Kensil, C. R., Daddona, P. E., and Fix, J. A., Enhancement of intestinal model compound transport by DS-1, a modified Quillaja saponin. J. Pharm. Sci., 87, 1395-1399 (1998) https://doi.org/10.1021/js9800735
  6. Choksakulnimitr, S., Masuda, S., Tokuda, H., Takakura, Y., and Hashida, M., In vitro cytotoxicity of macromolecules in different cell culture systems. J. Control. Release, 34, 233-241 (1995) https://doi.org/10.1016/0168-3659(95)00007-U
  7. Dal Pozzo, A., Acquasaliente, M., Geron, M. R., and Andriuoli, G., New heparin complexes active by intestinal absorption: I-multiple ion pairs with basic organic compounds. Thromb. Res., 56, 119-124(1989) https://doi.org/10.1016/0049-3848(89)90014-5
  8. Engel, R. H. and Fahrenbach, M. J., Intestinal absorption of heparin in the rat and gerbil. Proc. Soc. Exp. Biol. Med., 129, 772-777 (1968) https://doi.org/10.3181/00379727-129-33422
  9. Kang, S. S. and Woo, W. S., Two new saponins from Phytolacca americana. Planta Med., 53, 338-340 (1987) https://doi.org/10.1055/s-2006-962732
  10. Kang, S. S. and Woo, W. S., Phytolaccoside I, a new saponin from Phytolacca americana. Fitoterapia, LXII, 532-533 (1991)
  11. Kim, B. T., Kim, W. S., Kim, Y. S., Linhardt, R. J., and Kim, D. H., Purification and characterization of a novel heparinase from Bacteroides stercoris HJ-15. J. Biochem. (Tokyo), 128, 323-328 (2000) https://doi.org/10.1093/oxfordjournals.jbchem.a022756
  12. Kim, T. D., Sakon, M., Kawasaki, T., Kambayashi, J., Ohshiro, T., and Mori, T., Studies on liposome-encapsulated heparin. Thromb. Res., 43, 603-612 (1986) https://doi.org/10.1016/0049-3848(86)90097-6
  13. Koh, T. Y. and Bharucha, K. R., Intestinal absorption of stable heparinic acid complexes. J. Lab. Clin. Med., 80, 47-55 (1972)
  14. Kusakabe, M., Sakakura, T., Nishizuka, Y., Sano, M., and Matsukage, A., Polyester wax embedding and sectioning technique for immunohistochemistry. Stain Technol., 59, 127-132 (1984) https://doi.org/10.3109/10520298409113845
  15. Leone-Bay, A., Paton, D. R., Freeman, J., Lercara, C., O'Toole, D., Gschneidner, D., Wang, E., Harris, E., Rosado, C., Rivera, T., DeVincent, A., Tai, M., Mercogliano, F., Agarwal, R., Leipold, H., and Baughman, R. A., Synthesis and evaluation of compounds that facilitate the gastrointestinal absorption of heparin. J. Med. Chem., 41, 1163-1171 (1998) https://doi.org/10.1021/jm970811m
  16. Liu, D. Z., LeCluyse, E. L., and Thakker, D. R., Dodecylphosphocholine-mediated enhancement of paracellular permeability and cytotoxicity in Caco-2 cell monolayers. J. Pharm. Sci., 88, 1161-1168 (1999) https://doi.org/10.1021/js990094e
  17. Merchant, Z. M., Kim, Y. S., Rice, K. G., and Linhardt, R. J., Structure of heparin-derived tetrasaccharides. Biochem. J., 229, 369-377 (1985) https://doi.org/10.1042/bj2290369
  18. Narai, A., Arai, S., and Shimizu, M., Rapid decrease in transepithelial electrical resistance of human intestinal Caco-2 cell monolayers by cytotoxic membrane perturbents. Toxicol. in Vitro, 11, 347-354 (1997) https://doi.org/10.1016/S0887-2333(97)00026-X
  19. Onning, G., Wang, Q., Westrom, B. R., Asp, N. G., and Karlsson, B. W., Influence of oat saponins on intestinal permeability in vitro and in vivo in the rat. Br. J. Nutr., 76, 141-151 (1996) https://doi.org/10.1079/BJN19960016
  20. Rivera, T. M., Leone-Bay, A., Paton, D. R., Leipold, H. R., and Baughman, R. A., Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate: pharmacological considerations. Pharm. Res., 14, 1830-1834 (1997) https://doi.org/10.1023/A:1012160703533
  21. Sasaki, H., Yamamura, K., Mukai, T., Nishida, K., Nakamura, J., Nakashima, M., and Ichikawa, M., Modification of ocular permeability of peptide drugs by absorption promoters. Biol. Pharm. Bull., 23, 1524-1527 (2000) https://doi.org/10.1248/bpb.23.1524
  22. Sue, T. K., Jaques, L. B., and Yuen, E., Effects of acidity, cations and alcoholic fractionation on absorption of heparin from gastrointestinal tract. Can. J. Physiol. Pharmacol., 54, 613-617 (1976) https://doi.org/10.1139/y76-084
  23. Sung, M. K., Kendall, C. W., and Rao, A. V., Effect of soybean saponins and Gypsophila saponin on morphology of colon carcinoma cells in culture. Food Chem. Toxicol., 33, 357-366 (1995) https://doi.org/10.1016/0278-6915(95)00007-O
  24. Thanou, M., Nihot, M. T., Jansen, M., Verhoef, J. C., and Junginger, H. E., Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci., 90, 38-46 (2001) https://doi.org/10.1002/1520-6017(200101)90:1<38::AID-JPS5>3.0.CO;2-3
  25. Tidball, C. S. and Lipman, R. I., Enhancement of jejunal absorption of heparinoid by sodium ethylendiaminetetraacetate in the dog. Proc. Soc. Exp. Biol. Med., 111, 713-715 (1962) https://doi.org/10.3181/00379727-111-27900
  26. Ueno, M., Nakasaki, T., Horikoshi, I., and Sakuragawa, N., Oral administration of liposomally-entrapped heparin to beagle dogs. Chem. Pharm. Bull., 30, 2245-2247 (1982) https://doi.org/10.1248/cpb.30.2245
  27. Ward, P. D., Tippin, T. K., and Thakker, D. R., Enhancing paracellular permeability by modulating epithelial tight junctions. Pharm. Sci. Technol. Today, 3, 346-358 (2000) https://doi.org/10.1016/S1461-5347(00)00302-3
  28. Winsor E., and Cronheim, G. E., Gastro-intestinal absorption of heparin and heparinoids. Nature, 190, 263-264 (1961) https://doi.org/10.1038/190263a0
  29. Woo, W. S., Kang, S. S., Wagner, H., Seligmann, O., and Chari, V. M., Triterpenoid saponins from the roots of Phytolacca americana. Planta Med., 34, 87-92 (1978) https://doi.org/10.1055/s-0028-1097419
  30. Wu, S. J., Chun, M. W., Shin, K. H., Toida, T., Park, Y., Linhardt, R. J., and Kim, Y. S., Chemical sulfonation and anticoagulant activity of acharan sulfate. Thromb. Res., 92, 273-281 (1998) https://doi.org/10.1016/S0049-3848(98)00146-7