Efficacy of orally active chemical conjugate of low molecular weight heparin and deoxycholic acid in rats, mice and monkeys.
Deoxycholic acid (DOCA) is a bile acid that facilitates the gastrointestinal (GI) absorption of low molecular weight heparin (LMWH) by bonding chemically to it. The calculated coupling ratio and bioactivity of LMWH-DOCA was 3.6 and 126.8 IU/mg, respectively. This study examined the efficacy of orally administered LMWH-DOCA in rat, mouse and monkey models. When 100 mg/kg (12,680 IU/kg) of LMWH-DOCA was administered to rats or mice, its maximum anti-factor Xa activity was 0.76+/-0.15 and 0.15+/-0.03 IU/ml, respectively. On the other hand, when a single dose of 100 mg/kg LMWH-DOCA mixed with either a bile solution or 200 mg/kg free DOCA was administered to mice, the anti-factor Xa activity of LMWH-DOCA was 0.42-0.45 IU/ml. Fluorescence studies confirmed that the free bile acid induced the morphological change in LMWH-DOCA in the buffer solution. In the monkey experiments, the bioavailability of LMWH-DOCA after administering 200 mg/kg free DOCA orally was 6.8%, which was 8 times higher than that of LMWH (0.8%) and 4 times higher than that of LMWH-DOCA in the absence of free DOCA (1.7%). The absorption of orally administered LMWH-DOCA occurred in all parts of the small intestine, particularly in the ileum without causing any damage such as fusion of the microvilli and dissolution or disorientation of the cell layers. The optimum oral formulation for LMWH-DOCA delivery in each animal model was determined according to the different absorption behavior of LMWH-DOCA.
Lee
Yong-kyu
YK
Department of Chemical and Biological Engineering, Chungju National University, Chungbuk 380-702, Korea.
Kim
Sang Kyoon
SK
Lee
Dong Yun
DY
Lee
Seulki
S
Kim
Choong-Yong
CY
Shin
Ho-Chul
HC
Moon
Hyun Tae
HT
Byun
Youngro
Y
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; C521279:LMWH-DOCA conjugate; D003840:Deoxycholic Acid