title: Absorption study of deoxycholic acid-heparin conjugate as a new form of oral anti-coagulant.
abstract: The oral delivery of macromolecules is a topic of much interest as this would undoubtedly improve patient acceptance and compliance with chronic regimens. Heparin and insulin are perhaps among the first candidates that should be considered for oral macromolecule delivery systems. Heparin is the most potent anti-coagulant known for the prevention of deep vein thrombosis and pulmonary embolism, and an orally active heparin would undoubtedly effectively reduce chronic thrombotic events. Here, we report on the development of an orally administrable chemical conjugate of heparin and hydrophobic deoxycholic acid (DOCA), which we refer to as LHD. LHD was pre-formulated with dimethyl sulfoxide (DMSO) as solubilizer to further improve its oral bioavailability (9.1% in monkey). LHD was found to be absorbed mainly in the jejunum and ileum of the small intestine, although it is in the ileum that the absorption is most notable. From the mechanism studies of LHD absorption using Caco-2 cell monolayers for mimicking the intestine, we found that LHD highly permeated by passive diffusion through the transcellular route and its permeation was partially affected by bile acid transporters. This study demonstrates the feasibility of chemically modified heparin for long-term oral administration as an effective therapy for venous thromboembolism in clinical trials.
authors.affiliation: Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Sang Kyoon
authors.initials: SK
authors.lastname: Kim
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Lee
authors.forename: Eunhye
authors.initials: E
authors.lastname: Lee
authors.forename: Yong-kyu
authors.initials: YK
authors.lastname: Lee
authors.forename: Choong Yong
authors.initials: CY
authors.lastname: Kim
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Moon
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004058:Diffusion; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005240:Feasibility Studies; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D027981:Symporters / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; C521279:LMWH-DOCA conjugate; D029363:Organic Anion Transporters, Sodium-Dependent; D012997:Solvents; D027981:Symporters; D003840:Deoxycholic Acid; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D015951:Factor Xa; D004121:Dimethyl Sulfoxide