Long-term persistence of biological activity following administration of Enoxaparin sodium (clexane) is due to sequestration of antithrombin-binding low molecular weight fragments--comparison with unfractionated heparin.
We have previously reported (Brieger D, Dawes J. Thromb Haemost 1994; 72: 275-80) that the prolonged anti-Xa amidolytic activity following intravenous administration of the low molecular weight heparin Enoxaparin sodium is mediated by small molecules derived from the injected drug, and an antithrombin binding penta/hexasaccharide can be detected in the circulation as late as 1 week after administration. To investigate the mechanism underlying this persistence we administered 125I-labelled fractions of Enoxaparin sodium and unfractionated 125I-heparin to rabbits. Both 125I-heparin and the radiolabeled high molecular weight (> 6000 Da) Enoxaparin sodium were more effectively cleared from the circulation than the smaller components of LMW heparin. However, our data suggest that the circulating biologically active penta/hexasaccharide was not an unmodified component of the injected drug but was derived from a subpopulation of molecules of intermediate molecular weight (1800-6000 Da) which was retained in the tissues. Significant quantities of both Enoxaparin sodium and unfractionated heparin were retained in the internal organs. We propose that the sequestered subpopulations of Enoxaparin sodium and unfractionated heparin follow different catabolic routes. After administration of both unfractionated and LMW heparin additional antithrombin binding material was released into the circulation by a bolus dose of heparin. This material was not contained on circulating blood cells and was probably sequestered on the endothelium.
Brieger
D
D
Applied Research Group, Heart Research Institute, Sydney, Australia.
Dawes
J
J
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000493:pharmacokinetics*; D000990:Antithrombin III / Q000378:metabolism*; D017984:Enoxaparin / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006493:Heparin / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D011817:Rabbits
D000925:Anticoagulants; D017984:Enoxaparin; D007457:Iodine Radioisotopes; D000990:Antithrombin III; D006493:Heparin