ALTERED PHARMACOKINETIC PROPERTIES OF A LIPOPHILICALLY DERIVATIZED LOW-MOLECULAR-WEIGHT HEPARIN IN RATS

A new generation of lipophilic heparins has been developed that show l onger-lasting inhibitory effects on the coagulation system. We have st udied the radiopharmacokinetics of a derivatized low-molecular-weight heparin (LMWH) with a residualizing lipophilic tyramine-deoxysorbitol label in comparison with conventional LMWH after intravenous applicati on into Wistar rats. Whole body scintigraphy and analysis of the blood and organ distribution of different tracer preparations revealed that the lipophilically derivatized LMWH substance was predominantly trapp ed in the liver RES by a scavenger receptor-mediated mechanism. After the saturable uptake mechanism was blocked by maleylated bovine serum albumin, 41.4% of the lipophilic LMWH tracer circulated in blood, as c ompared with 18.4% of the control and 1% of conventional LMWH. The sam e results were attained by a competition experiment with on excess of unfractionated heparin. Urinary excretion of the lipophilic tracer amo ng the rats in this competition experiment was considerably lower (13. 7%) as compared with conventional LMWH (53.0%). Experiments with lipop hilic LMWH tracer bound nonspecifically to rat serum albumin confirmed that the prolonged half-life might in part be due to an increased aff inity for albumin. About 59% of the activity of the lipophilic tracer bound to albumin was found in the liver reticuloendothelial system, an d only 3.3% were excreted to urine 3 hours after injection. Further st udies are necessary to evaluate the accumulation rates and the metabol ic fate of lipophilically derivatized heparins in the case of an imped ed reticuloendothelial system uptake before attempts are made to thera peutically apply these compounds.