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(Circulation. 2001;104:3116.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Conjugation of Low-Molecular-Weight Heparin and Deoxycholic Acid for the Development of a New Oral Anticoagulant Agent

Yong-kyu Lee, MSc; Jong Hee Nam, MD; Ho-Chul Shin, DVM PhD; Youngro Byun, PhD

From the Department of Materials Science and Engineering, Kwangju Institute of Science and Technology (Y.L., Y.B.), and Department of Pathology, School of Medicine, Chonnam National University (J.H.N.), Gwangju, and the Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon (H.-C.S.), Korea.

Correspondence to Youngro Byun, PhD, Department of Materials Science and Engineering, Kwangju Institute of Science and Technology, 1 Oryong-dong, Puk-gu, Gwangju 500-712, Korea. E-mail yrbyun{at}kjist.ac.kr

Background— Heparin administration is usually limited to intravenous or subcutaneous injection. Oral delivery of heparin is an alternative to this and has been in great demand for treating patients who are at a high risk of deep vein thrombosis or pulmonary embolism. In this study, new heparin derivatives were synthesized to enhance the oral absorption of heparin in the gastrointestinal tract.

Methods and Results— By using heparin of 3000 Da [LMWH(3 kDa)], heparin of 6000 Da [LMWH(6 kDa)], and unfractionated heparin (UFH), we synthesized 3 kinds of conjugates of heparin and deoxycholic acid (DOCA): LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA. After oral administration of 100 mg/kg of heparin-DOCA, the maximum activated partial thromboplastin times of the LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 31.0±6.0, 87.8±11.1, and 51.0±8.7 seconds, respectively. The peak plasma concentrations of LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 0.06±0.02, 0.76±0.15, and 0.41±0.13 IU/mL, respectively. The bioavailability of LMWH(6 kDa)-DOCA at the 20-mg/kg dosage was calculated to be 7.8%.

Conclusions— LMWH(6 kDa)-DOCA was found to have a high anticoagulant effect when administered orally and could be used as a new oral anticoagulant agent. Furthermore, the present work proposed a new method for oral delivery of macromolecules and polysaccharide drugs.

Key Words: heparin • deoxycholic acid • conjugates • drugs

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