Synthetic Analogues of the Antithrombin III– Binding Pentasaccharide Sequence of Heparin

The synthetic pentasaccharide Org 31540/SR 90107A represents the antithrombin III (ATIII) binding region of heparin and accelerates the ATIII-mediated inhibition of coagulation factor Xa. This compound and 15 structural analogues with ATIII binding constants (K d ) ranging from 2.7 to 2600 nmol/L were compared for their plasma elimination in rats as measured from their factor Xa inhibiting activity. After administration of a low dose (100 nmol/kg body wt IV), each pentasaccharide showed a characteristic plasma half-life varying from a minimum of 0.3 hour for pentasaccharides with low affinity for ATIII to 10.9 hours for pentasaccharides with high affinity for the protein. The latter value was close to the half-life measured for radioiodinated rat ATIII (11.8 hours). We hypothesized that the elimination half-life of pentasaccharides is markedly extended by ATIII binding, of which the extent is governed by theK d of the complex. The following observations support this hypothesis. The low-dose, low-affinity pentasaccharides were almost fully recovered in the urine without having lost anti–factor Xa activity, whereas compounds with high ATIII binding affinity were only partly recovered in the urine. With a high dose (500 nmol/kg body wt), a rapid plasma clearance of pentasaccharide was observed until a concentration similar to that of endogenous ATIII was reached, in accordance with their expected 1:1 stoichiometric interaction. The elimination half-life was similar to that of the low dose. The relation betweenK d values and plasma half-lives could be explained by assuming rapid clearance of free and coclearance of ATIII-bound pentasaccharide with the protein. We applied the plasma ATIII concentration (3.5 μmol/L), the half-life of ATIII (11.8 hours), the half-life of unbound pentasaccharides (<10 minutes), and theK d values and concluded that highly specific binding to ATIII in the circulation governs the presented straightforward pharmacological profile for the pentasaccharides.