Metabolism of Sodium Pentosan Polysulphate in Man – Catabolism of Iodinated Derivatives

Summary

An iodinated derivative of the heparin analogue SP54 has been prepared and used in conjunction with unlabelled SP54 to study the catabolism and organ distribution of this potential antithrombotic agent in healthy human volunteers. As observed previously with ¹²⁵I-heparin, we found that the ¹²⁵I-SP54 was rapidly cleared from the circulation, returning later in a desulphated form. Organ distribution studies with ¹²³I-SP54 suggested that the liver and spleen were major sites of desulphation. Gel filtration and Polybrene binding showed the presence of sulphated macromolecular SP54 and desulphated macromolecular and depolymerised SP54 in post-injection urines. No depolymerised material was present in plasma suggesting depolymerisation occurs in the kidney.

Keywords

Heparin analogue - SP54 - Metabolism - Iodinated derivatives - Organ distribution

• References

• 1 Thomas DP, Lane DA, Michalski R, Johnson EA, Kakkar VV. A heparin analogue with specific action on antithrombin III. Lancet 1977; 1: 120-122
• 2 Lane DA, Michalski R, Van Ross ME, Kakkar VV. Comparison of heparin and a semisynthetic heparin analogue, A 73025. Br J Haematol 1977; 37: 239-245
• 3 Thomas DP, Barrowcliffe TW, Johnson EA, Stocks J, Dawes J, Pepper DS. A heparin analogue that releases endogenous heparan sulphate. Thromb Haemostas 1979; 42: 418 (Abstr.)
• 4 Soria C, Soria J, Rychewaert JJ, Holmer E, Caen JP. Anticoagulant activities of a pentosane polysulphate: comparison with standard heparin and a fraction of low molecular weight heparin. Thromb Res 1980; 19: 455-463
• 5 Ryde M, Eriksson H, Tangen O. Studies on the different mechanisms by which heparin and polysulphated xylans (PZ 68) inhibit blood coagulation in man. Thromb Res 1981; 23: 435-445
• 6 Vinazzer H, Haas S, Stemberger A. Influence on the clotting mechanism of sodium pentosan polysulphate (SP54) in comparison to commercial beef lung sodium heparin. Thromb Res 1980; 20: 57-68
• 7 Bergqvist D, Nilsson IM. A sulphated polysaccharide - the effects in vivo and in vitro on the haemostatic system in healthy volunteers. Thromb Res 1981; 23: 309-315
• 8 Fischer AM, Merton RE, Marsh NA, Williams S, Gaffney PJ, Barrowcliffe TW, Thomas DP. A comparison of pentosan polysulphate and heparin II: Effects of subcutaneous injection. Thromb Haemostas 1982; 47: 109-113
• 9 Bergqvist D, Efsing HO, Hallbook T, Lindblad B. Prevention of postoperative thromboembolic complications: a prospective comparison between Dextran 70, Dihydroergotamin heparin and a sulphated polysaccharide. Acta Chir Scand 1980; 146: 559-568
• 10 Bergqvist D, Ljunger H. A comparative study of Dextran 70 and a sulphated polysaccharide in the prevention of postoperative thromboembolic complications. Br J Surg 1981; 68: 449-451
• 11 Dawes J, Pepper DS. Catabolism of low-dose heparin in man. Thromb Res 1979; 14: 845-860
• 12 Greenwood FC, Hunter WM, Glover JS. The preparation of ¹³¹I- labelled human growth hormone of high specific radioactivity. Biochem J 1963; 89: 114-123
• 13 Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin. Biochem Biophys Res Comm 1976; 69: 570-577
• 14 Cash JD, Gader AM A, Mulder JL, Cort JH. Structure activity relations in the fibrinolytic response to vasopressin in man. Clin Sci Molec Med 1978; 54: 403-409
• 15 Losito R, Barlow G, Lemieux E. ³H-heparin and antithrombin III in the isolated liver perfusion. Thromb Res 1977; 10: 83-89
• 16 de Swaart CA M, Sixma JJ, Andersson L-O, Holmer E, Verschoor L, Nijmeyer A. Kinetics in normal humans of anticoagulant activity, radioactivity and lipolytic activity after intravenous administration of (³⁵S) heparin and (³⁵S) heparin fractions. Scand J Haematol 1980; 25 Suppl (Suppl. 36) 50-63
• 17 Kitani T, Nagarajan SC, Shanberge JN. Effect of protamine on heparin-antithrombin III complexes - in vivo studies. Thromb Res 1980; 17: 375-382
• 18 Effeney JD, Case SA, Graziano C, Blaisdel FW. Distribution and clearance of radioactive heparin. Surg Forum 1979; 30: 198-199
• 19 Bethell GS, Ayers JS, Hancock WS, Hearn MT W. A novel method of activation of cross-linked agarose with 1,1-carbonyldiimidazole which gives a matrix for affinity chromatography devoid of additional charged groups. J Biol Chem 1979; 254: 2572-2574
• 20 Mahadoo J, Hiebert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1977; 12: 79-90
• 21 Farooqui AA. Sulfatases, sulfate esters and their metabolic disorders. Clin Chim Acta 1980; 100: 285-299
• 22 McAllister BM, Demis DJ. Heparin metabolism: isolation and characterisation of uroheparin. Nature 1966; 212: 293-294