Hepatic uptake of a modified low molecular weight heparin in rats.

Abstract

Fractionated and unfractionated heparins are widely used as antithrombotic agents. Because of their heterogeneous composition, it is difficult to study the pharmacokinetics of these drugs. We now report on a new method for labeling low molecular weight heparins with "31I by binding tyramine to the anhydromannose end of the molecules. We examined the pharmacokinetics of the compound by intravenous injection of '31I-tyramine-heparin into Wistar rats. About 18% of the activity was found in the liver, whereas 33% was detected in urine. Biological activity in terms of Factor Xa inhibition was measurable. Since evidence from cell culture experiments implies that reticuloendothelial cell system receptors might be involved in heparin metabolism, maleylated BSA, a substance known to block scavenger receptors, was injected before the radiolabeled heparin compound. The liver uptake was reduced from 17.4 to 4.8%. Injection of unfractionated heparin before tracer application caused a considerable increase in urine excretion of the tracer substance. To our knowledge, this is the first report that liver uptake of heparins is linked to scavenger receptor mediated mechanisms in vivo. This interaction of heparins with scavenger receptors might play an important role in the biology of the vessel wall. (J. Clin. Invest. 1992Invest. .90:2110Invest. -2116

Characteristics of Tissue Distribution of Various Polysaccharides as Drug Carriers: Influences of Molecular Weight and Anionic Charge on Tumor Targeting

“…This was true for low molecular weight heparin, which is taken up by a scavenger receptor in the liver. 38) HA showed high liver distribution and cleared the circulatory system very rapidly, confirming previous findings that HA is rapidly absorbed by liver endothelial cells via receptor-mediated endocytosis.…”

Clearance of Adenovirus by Kupffer Cells Is Mediated by Scavenger Receptors, Natural Antibodies, and Complement

“…Neither poly(A) nor heparin is a broad-spectrum SR inhibitor. Nonetheless, both poly(A) and heparin have previously been shown to inhibit the uptake of a select subset of SR ligands by macrophages both in vitro and in vivo (15,53,58,65). Of note is that the experiment shown in Fig.…”

“…We found that poly(A) and heparin caused a partial reduction of Ad uptake by KCs, although this was statistically significant only for poly(A). Both poly(A) and heparin are known to inhibit the clearance of distinct subsets of SR ligands, apparently by binding to only a subset of SRs (15,53,58,65). Since a reduction in the amount of Ad taken up by KCs should increase the availability of Ad to other tissues, we also tested selected SR ligands for their ability to enhance Ad transduction of hepatocytes in vivo.…”

Liver sinusoidal endothelial cells are the principal site for elimination of unfractionated heparin from the circulation

“…Most previous studies have used iodinated (3,65) or tritiumlabeled heparin (11,73,77) for metabolic studies of heparin and assessment of organ distribution by autoradiography and recovered radioactivity in isolated organs. However, FITClabeled UFH has also been shown to be suitable for studying heparin distribution and metabolism (11).…”