We have recently presented evidence that a macrophage scavenger receptor-mediated
pathway is responsible for the hepatic uptake of unfractionated heparins and low-molecular-weight
heparins (LMWHs) in the rat. The same receptor-mediated pathway was partially responsible
for the removal of oxidized low-density lipoprotein. Unfractionated and fractionated
LMWHs exert their anticoagulatory effects predominately by reversibly binding to the
plasma glycoprotein antithrombin III. In this study LMWHs modified by endpoint attachment
of tyramine were radiolabeled and their fractions with low or high affinity to AT-III
studied in vivo in rats. The high-affinity fraction was predominately cleared from
the circulation by a hepatic uptake mechanism. About 25% of the injected high-affinity
tracer material was recovered, whereas only about 8% of the low-affinity material
was found in the liver after 180 minutes. Blocking the scavenger receptor-mediated
liver RES uptake mechanism by maleylated bovine serum albumin led to a considerable
decline in liver uptake (9 versus 25%). The low-affinity material was rapidly eliminated
into the urine after 180 minutes. About 45% of the low-affinity material was excreted
versus 23% of the high-affinity material. Tight binding to AT-III prevented LMWH-tyramine
from being rapidly cleared from the circulation via the kidneys into the urine; instead,
the scavenger receptor-mediated hepatic uptake mechanism seemed to be more dominant
in removing material with high affinity to AT-III from blood.
Scavenger receptor - antithrombin III - heparins-pharmacology - heparins-pharmacokinetics
- hepatic metabolism - low-molecular-weight-heparintyramine
