Pharmacokinetics of Dermatan Sulfate in the Rabbit After Intravenous Injection

Summary

To investigate the pharmacokinetic properties of dermatan sulfate (DS), a new potential antithrombotic agent, two different approaches were used. In the first one, DS was derivatized with 3-4 hydroxyphenyl propionic acid N hydroxysuccinimide ester (SHPP) and iodinated. The labelled derivative was injected by IV route to rabbits with increasing doses of unlabelled compound ranging from 20 to 4000 μg/kg. The disappearance of DS from plasma was characterized by measuring both the circulating radioactivity and the biological activity using an original assay based upon the catalysis of heparin cofactor II – thrombin formation. The radioactivity data indicated that the volume of distribution, the clearance and the half life of the tracer were independent of the dose of DS injected. DS concentrations measured by the bioassay indicated that more than 90% were cleared with half lives close to those calculated from the radioactivity data; the remaining biological activity was cleared at a slower rate. Experiments performed with bi-nephrectomized animals indicated that the kidneys play a major role in the elimination of DS or of its metabolites which may have a residual biological activity. In the second set of experiments, unlabelled DS was delivered under continuous intravenous infusion for 5 hours at 5 increasing doses ranging from 160 to 4200 μg/kg/h. The biological activities were used to measure the plateau concentration of DS: there was a linear relationship between the dose delivered and the plasma concentration. These data indicate that the pharmacokinetic profile of DS is very close to that of low molecular weight heparin, and quite different from that of SH.

Keywords

Dermatan sulfate - Pharmacokinetics

• References

• 1 Tollefsen DM, Pestka CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 1983; 258: 6713-6716
• 2 Buchanan MR, Boneu B, Ofosu F, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin. Blood 1985; 65: 198-201
• 3 Fernandez F, Van Ryn J, Ofosu F, Hirsh J, Buchanan MR. The haemorrhagic and antithrombotic effects of dermatan sulfate. Brit J Haematol 1986; 64: 309-317
• 4 Boneu B, Caranobe C, Gabaig AM, Dupouy D, Sie P, Buchanan MR, Hirsh J. Evidence for a saturable mechanism of disappearance of standard heparin in rabbits. Thromb Res 1987; 46: 835-844
• 5 Boneu B, Buchanan MR, Caranobe C, Gabaig AM, Dupouy D, Sie P, Hirsh J. The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits. Thromb Res 1987; 46: 845-853
• 6 Dawes J, Pepper DS. Catabolism of low-dose heparin in man. Thromb Res 1979; 14: 845-860
• 7 Greenwood FC, Hunter WM, Glovers JS. The preparation of ¹³¹I. Labelled human growth hormone of high specific radioactivity. Biochem J 1963; 89: 114-121
• 8 Refn I, Vestergaard L. The titration of heparin with protamine. Scand J Clin Lab Invest 1954; 6: 284-292
• 9 Dol F, Sie P, Dupouy D, Boneu B. Effect of pentosan polysulfate administration in man on the formation of covalent complexes between heparin cofactor II and thrombin generated in plasma by contact activation. Thromb Haemostas 1986; 56: 295-298
• 10 Gomeni C, Gomeni R. I G Pharm: interactive graphic package for pharmacokinetics analysis. Comput Biomed Res 1978; 11: 345-351
• 11 De Swart CA M, Nijmeyer B, Roelofs JM M, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60: 1251-1258
• 12 Caranobe C, Barret A, Gabaig AM, Dupouy D, Sié P, Boneu B. Disappearance of circulating anti-Xa activity after intravenous injection of standard heparin and of a low molecular weight heparin (CY 216) in normal and nephrectomized rabbits. Thromb Res 1985; 40: 129-133
• 13 Goudable C, Ton That H, Damani A, Durand D, Caranobe C, Sie P, Boneu B. Low molecular weight heparin half life is prolonged in haemodialysed patients. Thromb Res 1986; 43: 1-5