Evaluation of the Oral Absorption of Heparin Conjugated with Sodium Deoxycholate as a Facilitating Agent in GI Tract

Hyun Tae Moon; Ok Chul Jeon; Youngro Byun; Yu Jin Kim; Yong-Kyu Lee

Macromolecular Research, Vol.17, No.2, 79-83, February, 2009

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Evaluation of the Oral Absorption of Heparin Conjugated with Sodium Deoxycholate as a Facilitating Agent in GI Tract

Hyun Tae Moon, Ok Chul Jeon¹, Youngro Byun², Yu Jin Kim³, and Yong-Kyu Lee^{3, †}

Mediplex Corp., Seoul 135-729, Korea
¹Department of Textile Engineering, Kyung Hee University, Gyeonggi 449-701, Korea
²College of Pharmacy, Seoul National University, Seoul 151-742, Korea
³Department of Chemical and Biological Engineering, Chungju National University, Chungbuk 380-702, Korea

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The oral delivery of heparin is the preferred therapy in the treatment of patients with a high risk of deep vein thrombosis and pulmonary embolism. New conjugates of heparin and sodium deoxycholate were synthesized in order to enhance the heparin absorption in the GI tract. After oral administration of DOC-heparin, the concentration in anti-FXa assay was increased with increasing amount of coupled DOC. The maximum concentration of DOC-heparin VIII conjugate was 3.3±0.5 IU/mL at an oral dose of 10 mg/kg, which was 3-fold higher than the baseline level. Finally, DOC coupled to heparin greatly enhanced the absorption of heparin in the GI tract, and this enhancing effect was not induced by changing the tissue structure of the GI wall.

Keywords:sodium deoxycholate;oral delivery;heparin;conjugate.

[References]

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Rosenberg RD, Semin. Hematol., 34, 2 (1997)
Pineo GF, Hull RD, Curr. Concepts. Thromb., 82, 587 (1998)
Gonze MD, Manord JD, Leone-Bay A, Baughman RA, Garrard L, Sternbergh III WC, Money SR, Am. J. Surg., 176, 176 (1998)
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Caramazza ID, Atri G, Bossi ML, Deponti FD, Angelo L, Crema A, Thromb. Res., 62, 785 (1991)
Morton AK, Edwards HE, Allen JC, Philips GO, Int. J. Pharm., 9, 321 (1982)
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Engel RH, Riggi SJ, Proc. Soc. Exp. Biol. Med., 130, 706 (1969)
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Leone-Bay A, Paton DR, Weidner JJ, Med. Res. Rev., 20, 169 (2000)
Lee Y, Moon HT, Byun Y, Thromb. Res., 92, 149 (1998)
Lee Y, Kim SH, Byun Y, Pharm. Res., 17, 1259 (2000)
Lee Y, Nam JH, Shin H, Byun Y, Circulation, 104, 3116 (2001)
Cho KJ, Moon HT, Park GE, Jeon OC, Byun Y, Lee YK, Bioconjugate Chem., 19, 1346 (2008)
Kim S, Vaishali B, Lee E, Byun Y, Thromb. Res., 117, 419 (2006)
von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, et al., J. Med. Chem., 48, 2724 (2005)

[1] Damus PS, Hicks M, Rosenberg RB, Nature, 246, 355 (1977)

[2] Thompson-Ford JK, Pharmacotherapy, 18, 749 (1998)

[3] Rosenberg RD, Semin. Hematol., 34, 2 (1997)

[4] Pineo GF, Hull RD, Curr. Concepts. Thromb., 82, 587 (1998)

[5] Gonze MD, Manord JD, Leone-Bay A, Baughman RA, Garrard L, Sternbergh III WC, Money SR, Am. J. Surg., 176, 176 (1998)

[6] DalPozzo A, Acquasaliente M, Geron MR, Thromb. Res., 56, 119 (1989)

[7] Caramazza ID, Atri G, Bossi ML, Deponti FD, Angelo L, Crema A, Thromb. Res., 62, 785 (1991)

[8] Morton AK, Edwards HE, Allen JC, Philips GO, Int. J. Pharm., 9, 321 (1982)

[9] Sue TK, Jaque LB, Yuen E, Can. J. Physiol. Pharm., 54, 613 (1976)

[10] Engel RH, Riggi SJ, Proc. Soc. Exp. Biol. Med., 130, 706 (1969)

[11] Rivera TM, Leone-Bay A, Paton DR, Leipold HR, Baughman RA, Pharm. Res., 14, 1830 (1997)

[12] Leone-Bay A, Paton DR, Weidner JJ, Med. Res. Rev., 20, 169 (2000)

[13] Lee Y, Moon HT, Byun Y, Thromb. Res., 92, 149 (1998)

[14] Lee Y, Kim SH, Byun Y, Pharm. Res., 17, 1259 (2000)

[15] Lee Y, Nam JH, Shin H, Byun Y, Circulation, 104, 3116 (2001)

[16] Cho KJ, Moon HT, Park GE, Jeon OC, Byun Y, Lee YK, Bioconjugate Chem., 19, 1346 (2008)

[17] Kim S, Vaishali B, Lee E, Byun Y, Thromb. Res., 117, 419 (2006)

[18] von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, et al., J. Med. Chem., 48, 2724 (2005)