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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 (&lt;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.

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