Intestinal absorption of low molecular weight heparin in animals and human subjects.
BACKGROUND
We had previously shown that the use of bile salts, which act as surfactants, facilitates the intestinal absorption of large molecules such as those of heparin and insulin. However, the bioavailability of unfractionated heparin (UFH) administered through the large intestine was low. The aim of the present study was to evaluate the absorption of low molecular weight heparin (LMWH) combined with bile salts through the gut mucosa in animals and human subjects.


METHODS
LMWH (Fragmin, Kabi-Pharmacia, Stockholm) or UFH with or without sodium cholate (Sch) was administrated rectally in rats and healthy volunteers via a microenema. Absorption was estimated by the activated partial thromboplastin time (aPTT), the plasma anti-factor Xa activity and the plasma lipoprotein lipase (LPL) activation.


RESULTS
In groups of 6 rats, LMWH at doses of 100--1,000 U with sodium cholate (10--20 mg/ml) was readily absorbed through the gut mucosa, as indicated by both, anti-factor Xa levels of up to 1 U/ml and a dose-dependent activation of LPL. The absorption was significantly superior to that of UFH with Sch or LMWH given without Sch (p < 0.001). The plasma anti-factor Xa levels in the 6 healthy volunteers who received a microenema containing 25,000 U of LMWH with 20 mg/ml of Sch were 0.38 U/ml at 15 min and 0.1 U/ml at 240 min. LPL activation and aPTT prolongation were also observed in these subjects. The plasma LMWH levels after rectal application were in the same range as those obtained after subcutaneous administration, however the elimination time (t 1/2) was shorter. There were no adverse reactions.


CONCLUSIONS
Intestinal absorption of LMWH facilitated by Sch is both feasible and safe. A slow release formulation will be needed to prolong the plasma half-life.
Nissan
A
A
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.
Ziv
E
E
Kidron
M
M
Bar-On
H
H
Friedman
G
G
Hyam
E
E
Eldor
A
A
D000285:Administration, Rectal; D000328:Adult; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000494:pharmacology; D001682:Biological Availability; D017985:Dalteparin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D065427:Factor Xa Inhibitors; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051381:Rats; D020358:Sodium Cholate / Q000008:administration & dosage / Q000494:pharmacology
D000925:Anticoagulants; D001647:Bile Acids and Salts; D004338:Drug Combinations; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D008071:Lipoprotein Lipase; D020358:Sodium Cholate; D017985:Dalteparin