Pharmacodynamic Properties of Long Lasting Butyryl Heparin Derivatives in the Rabbit

Summary

This paper reports on the pharmacodynamic properties of butyryl derivatives of unfractionated heparin (C4-UH) and of low molecular weight heparin (C4-CY 216) after bolus intravenous injection, constant infusion and subcutaneous administration to rabbits. The pharmacodynamic properties of the two butyryl derivatives were compared to those of the parent compounds, unfractionated heparin (UH) and low molecular weight heparin (CY 216). After bolus intravenous injection of increasing doses, the disposition of the butyryl derivatives were comparable to that of their parent compounds up to 3 mg kg^-1. Over this dose, their clearances became 2 to 3 times lower. These long lasting properties were confirmed by constant intravenous infusion experiments. After subcutaneous administration, the bioavailability of C4-UH remained low (10%) at any dose while that of C4-CY 216 ranged from 42 to 120%. If these findings are confirmed in man, these new derivatives open the possibility of treating established deep vein thrombosis with only one daily injection of a butyryl derivative of low molecular weight heparin.

• References

• 1 Saivin S, Petitou M, Lormeau JC, Dupouy D, Sie P, Caranobe C, Houin G, Boneu B. Pharmacological properties of unfractionated heparin derivative with long lasting effect. J Lab Clin Med 1992; 119: 189-196
• 2 Saivin S, Petitou M, Lormeau JC, Dupouy D, Sie P, Caranobe C, Houin G, Boneu B. Pharmacological properties of a low molecular weight butyryl heparin derivative (C4-CY 216) with long lasting effects. Thromb Haemostas 1992; 67: 346-351
• 3 Boneu B, Caranobe C, Sie P. Pharmacodynamics of heparin and low molecular weight heparin. Baillieres Clin Haematol 1990; 3: 531-544
• 4 Briant L, Caranobe C, Saivin S, Sie P, Bayrou B, Houin G, Boneu B. Unfractionated heparin and CY 216: pharmacokinetics and bioavailabilities of the antifactor Xa and Antithrombin effects after intravenous and subcutaneous injection in the rabbit. Thromb Haemostas 1989; 61: 348-353
• 5 Petitou M, Coudert C, Level M, Lormeau JC, Zuber M, Simenel C, Fournier JP. Selectively O-acylated glycosaminoglycan derivatives. >Carbohydr Res. 1992 (in press)
• 6 De Swart CAM, Nijmeyer B, Roelofs JMM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60: 1251-1258
• 7 Dawes J, Pepper DS. Catabolism of low-dose heparin in man. Thromb Res 1979; 14: 845-860
• 8 Oh TH, Naidoo SS, Jaques LB. The uptake and disposition of 358-heparin by macrophages in vitro. J Reticuloendothel Soc 1973; 13: 134-142
• 9 Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976; 8: 195-204
• 10 Mahadoo J, Hiebert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1977; 12: 79-90
• 11 Piper J. The fate of heparin in rabbits after intravenous injection. Filtration and tubular secretion in the kidneys. Acta Pharmacol 1947; 3: 373-384
• 12 Caranobe C, Barret A, Gabaig AM, Dupouy D, Sie P, Boneu B. Disappearance of circulating anti Xa activity after intravenous injection of standard heparin and low molecular weight heparin (CY 216) in normal and nephrectomized rabbits. Thromb Res 1985; 40: 129-133
• 13 Palm M, Matsson C. Pharmacodynamics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal or metabolic clearance. Thromb Haemostas 1987; 58: 932-935
• 14 Barzu T, Van Rijn JL, Petitou M, Molho P, Tobelem G, Caen J. Endothelial binding sites for heparin. Biochem J 1986; 238: 847-854
• 15 Williams SP, Barrowcliffe TW. The effects of post-heparin plasma lipases on anti-Xa clotting activity. Thromb Res 1985; 37: 371-377
• 16 Hull R, Raskob G, Pineo G, Green D, Trowbridge A, Elliot G. and colleagues A randomized double-blind trial of low molecular weight heparin in the initial treatment of proximal vein thrombosis. Thromb Haemostas 1991; 65: 872