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DOI: 10.1055/s-0038-1646018
Pharmacokinetics of Heparin and Low Molecular Weight Heparin Fragment (Fragmin®) in Rabbits with Impaired Renal or Metabolic Clearance
Publication History
Received 09 April 1987
Accepted after revision 23 June 1987
Publication Date:
28 June 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/198703/lookinside/thumbnails/10-1055-s-0038-1646018-1.jpg)
Summary
The kinetics and tissue distribution of 3H-heparin and a 3H- labelled low molecular weight heparin fragment were compared in normal rabbits as well as in rabbits with blocked renal function or reticuloendothelial system (RES). Radioactivity in plasma, urine, liver and kidneys, as well as anti-FXa activity in plasma were determined. The plasma elimination of heparin was, when compared to normal controls, prolonged both in rabbits with renal dysfunction as well as in rabbits with blocked RES, while renal dysfunction was the only parameter that significantly prolonged the plasma half-life of Fragmin. Studies on tissue distribution in normal rabbits revealed that about 60 per cent of the radioactive heparin dose accumulated in the liver and kidney three hours after the injection, whereas the corresponding value was less than 10 per cent for the Fragmin-derived radioactivity. The recovery of radioactivity in urine within three hours was 5 and 35 per cent of the dose, respectively, for 3H-heparin and 3H- Fragmin. It is concluded from the present study that the rapid plasma elimination of heparin in the rabbit (tl/2 = 17 minutes) is mainly due to a high tissue distribution (liver and kidney) while the plasma elimination of Fragmin (t1/2 = 28 minutes) is mainly caused by renal excretion.
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References
- 1 de Swart C AM, Nijmeye B, Roclofs J MM, Sixma JJ. Kinetics of intravenous administered heparin in normal humans. Blood 1982; 60: 1251-1258
- 2 Hiehert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976; 8: 195-204
- 3 Mahadoo J, Hiebert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1977; 12: 79
- 4 Barzu T, Van Rijn JL, Petitou M, Molho P, Tobelem G, Caen IP. Endothelial binding sites for heparin: Specificity and role in heparin neutralization. Biochem J 1986; 238: 847-854
- 5 Hiebert L. The uptake of heparin by liver sinusoidal cells in normal and atherosclerotic rabbits. Thromb Res 1981; 21: 383-390
- 6 Oh TH, Naidoo SS, Jaques LB. The uptake and disposition of 3"S- heparin by macrophages in vitro. J Reticuloendothelial Soc 1973; 13: 134
- 7 Monkhouse F, Dickie H. Physiological factors concerned with the removal of injected heparin from the circulating blood. Amer J Physiol 1954; 178: 223-228
- 8 Losito R, Gattiker H, Bilodeau G. Heparin excretion in intact and hepatectomized rats. Thromb Res 1981; 21: 283-290
- 9 Caranobe C, Barret A, Gabaig AM, Dupouy D, Sie P, Boneu B. Disappearance of circulating anti-FX., 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
- 10 Holmer E, Mattsson C, Nilsson S. Anticoagulant and antithrombotic effects of heparin and low molecular weight heparin fragments in rabbits. Thromb Res 1982; 25: 475-485
- 11 Ockelford PA, Carter CJ, Mitchell J, Hirsh J. Discordance between the anti-Xa activity and the anti-thrombotic activity of an ultra-low molecular weight fraction. Thromb Res 1982; 28: 401-409
- 12 Bergqvist D, Hedncr U, Sjolin E, Holmer E. Antithrombotic effects of two types of low molecular weight heparin administered subcutaneously. Thromb Res 1983; 32: 381-391
- 13 Bara L, Billand E, Gramond G, Kehr A, Samama M. Comparative pharmacokinetics of a low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39: 631-636
- 14 Bratt Cj, Tornebohm E, Lockner D, Bergstrom K. A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment. Thromb Haemostas 1985; 53: 208-211
- 15 Hatton M WC, Berry LR, Machovich R, Regoeczi E. Tritiation of commercial heparins by reduction with NaB’H: chemical analysis and biological properties of the product. Annual Biochem. 1980; 106: 417-426
- 16 Benacerraf B, Biozzi G, Halpern N, Stiffel C, Mouton D. A study of the phagocytic activity of the reticulo-endothelial system toward heat denatured human serum albumin tagged with 1,11 and application of this method to measure liver blood flow. Brit J Exper Path 1957; 38: 35
- 17 Fraker P, Speck JC. Protein and cell membrane iodinations with a sparingly soluble chloroanride 1, 3, 4. 6-tetrachlora-3a 6a-diphenyl- glucoluril. Biochem Biophvs Res Commun 1978; 80: 849
- 18 Patel KR, Li MP, Baldeschwicler JD. Suppression of liver uptake of liposomes bv dextran sulphate 500. Proc Nat Acat Sci USA. 1983; 80: 6518-6522
- 19 Losito R, Barlow G, Lemieux E. TEheparin and antithrombin III in the isolated liver perfusion. Thromb Res 1977; 10: 83-93
- 20 Teien AM. Heparin elimination in patients with liver cirrhosis. Thromb Haemostas 1977; 38: 701-706
- 21 Barzu T, Molho P, Tobelem C, Petitou M, Caen J. Binding and endoevtosis of heparin by human endothelial cells in culture. Biochem. Biophvs. Acta. 1985; 345: 196
- 22 Palm M, Mattsson Ch. Pharmacokinetics of a low molecular weight heparin fragment (FragmiiT). A comparative study of its high- and low-affinity forms for antithrombin. (Submitted for publication).
- 23 Goudable C, Ton That H, Damani A, Dunand D, Caranobe C, Sie P, Boneu B. Low molecular weight heparin half-life is prolonged in hemodialyzed patients. Thromb Res 1986; 43: 1-5
- 24 Bonnet WM, Singer I, Coggins CJ. A guide to drug therapy in renal failure. J Am Med Ass 1974; 230: 1544-1553
- 25 Perry PJ, Herron GR, King JC. Heparin half-life in normal and impaired renal function. Clin. Pharm. Thor. 1974; 15: 514-519