Pharmacokinetics of New Synthetic Heparin Mimetics

Summary

Pharmacokinetics of oligosaccharides displaying various affinities for antithrombin (AT) allowed us to show that there was a close relationship between the plasma half-life of these antithrombotic oligosaccharides and their affinity for AT. Recently, we have described new heparin mimetics comprising an AT binding domain and a thrombin binding domain separated by a neutral methylated saccharide sequence. These compounds displayed strong anti-Xa and anti-IIA activities and, in contrast to heparin, escaped neutralisation by platelet factor 4. The aim of this work was to compare the pharmacokinetics of several of these heparin mimetics in rats. These compounds differed by their length, charge and affinity for AT (AT-binding domain). The results obtained indicate that the prolongation of the AT binding domain did not modify significantly their affinities for AT. However, an increase in the number of charges leads to a decrease in the half-life. When a methylated spacer was added in order to minimise the non-specific interactions to other proteins, half-lives of the heparin mimetic were in the same range than that of the pentasaccharide used as an AT binding domain.

In conclusion, this study shows the influence of the charge of the oligosaccharides on their pharmacokinetics and underlines the importance of minimising their non-specific binding to plasma proteins in order to obtain compounds with predictive pharmacokinetics.

Keywords

Antithrombin - heparin - pentasaccharide

• References

• 1 Fareed J, Fu K, Yang LH, Hoppenstead D. Pharmacokinetics of low molecular weight heparin in animal models. Semin Thromb Haemost 1999; 25: 51-5.
• 2 Cornelli U, Fareed J. Human pharmacokinetics of low molecular weight heparins. Semin Thromb Haemost 1999; 25: 57-61.
• 3 Linhardt RJ, Toida T. Heparin oligosaccharides: New analogues – development and application. In: Wietczak ZJ, Nieforth KA. eds Carbohydrate in drug design. New York: Marcel Dekker; 1997: 277-341.
• 4 Linhardt RJ. Heparin: an important drugs enters its seventh decade. Chem Indust 1991; 02: 45-50.
• 5 Barrowcliffe TW. Low molecular weight heparin (s). Br J Haematol 1995; 90: 362-71.
• 6 Briant L, Caranobe C, Saivin S, Sié P, Bayrou B, Houin G, Boneu B. Unfractionated heparin and CY216: Pharmacokinetic and bioavaibilities of the anti-Xa and antithrombotic effects after intravenous and subcutaneaous injection in the rabbit. Thromb Haemost 1989; 61: 348.
• 7 Green D, Hirsh J, Heit J, Prins M, Davidson B, Lensing AW. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacological Reviews 1994; 46: 89-109.
• 8 Carrié D, Caranobe C, Boneu B. A comparison of the antithrombotic effects of heparin and low molecular weight heparins with increasing antifactor Xa/antifactor IIa ratio in the rabbit. Br J Haematol 1993; 83: 622.
• 9 Herbert JM, Petitou M, Lormeau JC, Cariou R, Necciari J, Magnani HM, Zandberg P, Van Amsterdam RGM, Van Boeckel CAA, Meuleman DG. SR90107A/Org31540, a novel anti-factor Xa antithrombotic agent. Cardiovascular drug reviews 1997; 01: 1-26.
• 10 Herbert JM, Hérault JP, Bernat A, van Amsterdam RGM, Lormeau JC, Petitou M, van Boeckel C, Hoffmann P, Meuleman DG. Biochemical and pharmacological properties of SANORG 34006, a potent and longacting synthetic pentasaccharide. Blood 1998; 11: 4197-205.
• 11 Buller HR, Cariou R, Gallus A, Gent M, Ginsberg J, Prins MH, Lensing A, Levi M, Nurmohammed N, Hirsh J, Roberts R, ten Cate JW, Decousus H, Mismetti P, Buchmuller A, Charlet V, Viallon A, van der Meer J, Meinardi JR, Meijer K, Piovella F, Barone M, Beltrametti C, Serafini S, Kraaijenhagen RA. et al. Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ORG31540) with pure anti-factor Xa activity – A phase II evaluation. Circulation 2000; 102: 2726-31.
• 12 Van Amsterdam R, Vogel G, Visser A, Kop WJ, Buiting MT, Meuleman DG. Synthetic analogues of the antithrombin III-binding pentasaccharide sequence of heparin. Prediction of in vivo residence times. Arter, Thromb and Vasc Biol 1995; 15: 495-503.
• 13 Petitou M, Duchaussoy P, Driguez PA, Hérault JP, Lormeau JC, Herbert JM. New Synthetic Heparin Mimetics Able to Inhibit Thrombin and Factor Xa. Bioorg Med Chem Lett 1999; 09: 1155-60.
• 14 Petitou M, Duchaussoy P, Driguez PA, Hérault JP, Lormeau JC, Herbert JM. Synthetic Oligosaccharides Having Various Functional Domains: Potent and Potentially Safe Heparin Mimetics. Bioorg Med Chem Lett 1999; 09: 1161-6.
• 15 Petitou M, Hérault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398: 417-22.
• 16 Herbert JM, Hérault JP, Bernat A, Savi P, Schaeffer P, Driguez AP, Duchaussoy P, Petitou M. SR123781A, a synthetic heparin mimetic. Thromb Haemost 2001; 85: 852-60.
• 17 McKay A. A simple two-step procedure for the isolation of antithrombin III from biologicals fluids. Thromb Res 1981; 21: 375-82.
• 18 Atha DH, Lormeau JC, Petitou M, Rosenberg RD, Choay J. Contribution of 3-O- and 6-O-sulfated glucosamine residues in the heparin-induced conformational change in antithrombin III. Biochemistry 1987; 26: 6454-61.
• 19 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: Increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 10: 399-410.
• 20 Macarana M, Lindhal U. Mode of interaction between platelet factor 4 and heparin. Glycobiology 1993; 03: 271-7.
• 21 Stringer SE, Gallagher JT. Specific binding of the chemokine platelet factor 4 to heparan sulfate. J Biol Chem 1997; 272: 20508-14.
• 22 Mulloy B, Johnson EA. Assignment of the 1H-n.m.r. spectra of heparin and heparan sulphate. Carbohydrate Research 1987; 170: 151-65.
• 23 Brieger D, Dawes J. Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparin. Thromb Haemost 1997; 77: 317-22.
• 24 Peyrou V, Lormeau JC, Hérault JP, Boneu B, Herbert JM. Long-term persistence of low-molecular-weight material with anti-factor Xa activity contributes to anticoagulant and antithrombotic effects after subcutaneous injection of CY216 in the rabbit. Blood Coag and Fibrinol 1997; 08: 175-84.