Pharmacokinetics of fragmin. A comparative study in the rabbit of its high and low affinity forms for antithrombin.

A tritium-labelled low molecular weight heparin fragment with an average molecular weight of 4000-6000 (Fragmin), was fractionated into its high and low affinity forms for antithrombin. The fractions obtained were injected into rabbits, and the plasma half-life (t1/2) volume of distribution (Vd), area under the curve (AUC), total body clearance (TCl) and renal clearance (Clr) were determined. When followed by radioactivity, both the high and low affinity forms of Fragmin as well as Fragmin itself were eliminated from plasma in a biexponential manner. Values for AUC were very low compared to those expected from the given dose. This effect was most pronounced for low affinity-Fragmin demonstrating a significantly higher extravascular distribution of molecules lacking affinity for antithrombin. From radio activity data, it was also demonstrated that the fraction of dose that was eliminated from plasma via non-renal (cellular clearance) mechanisms was higher for heparin (95 per cent) than for Fragmin (77 per cent) after a dose of 100 micrograms/kg. This demonstrates that cellular clearance is of less importance in the plasma elimination of low molecular weight heparin fragment, an effect that may explain their longer plasma half-lifes despite the fact that they are more readily and faster excreated into the urine.