Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparins.
Low molecular weight (LMW) heparins have prolonged circulating half-lives relative to unfractionated heparin, but the rates of plasma clearance differ between different LMW preparations. To determine the impact of method of production on their pharmacokinetic and ex vivo biological properties, two LMW heparins of similar molecular weight distribution, Logiparin and Fragmin, were radiolabelled with 125I, administered intravenously with 4 mg/kg of carrier drug into rabbits, and the circulating radiolabelled material and anti-Xa activity were analysed by size exclusion chromatography and affinity for antithrombin and Polybrene. Following administration of Logiparin, the anti-Xa amidolytic activity was eliminated with the same half-life as the anti-thrombin-binding radiolabel and was not neutralised by antibody against tissue factor pathway inhibitor (TFPI). Larger molecules were cleared preferentially and were no longer detectable 8 h post injection. These findings resemble those we have previously described for Enoxaparin. After Fragmin administration the antithrombin binding radiolabel was cleared more rapidly than the anti-Xa activity, and at late times after injection a significant amount of this activity was neutralised by antibody against TFPI. Sulphated radiolabel was eliminated with a similar half-life to the anti-Xa activity and sulphated molecules > 6000 Da remained in the circulation 8 h after administration. Fragmin, unlike Logiparin and Enoxaparin, has no negatively charged sulphamino group at the reducing end of the molecule. We suggest that this minimises cellular interaction and protects the larger molecules from elimination. They remain in the circulation, contributing to anti-Xa activity by binding TFPI. Thus the method of production of LMW heparins may significantly influence their pharmacokinetic properties and circulating anticoagulant activities.
Brieger
D
D
Applied Research Group, Heart Research Institute, Sydney, Australia.
Dawes
J
J
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D002240:Carbohydrate Sequence; D002850:Chromatography, Gel; D017985:Dalteparin / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D017984:Enoxaparin / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005260:Female; D006207:Half-Life; D006495:Heparin, Low-Molecular-Weight / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D006583:Hexadimethrine Bromide / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011817:Rabbits; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D008074:Lipoproteins; C079002:Logiparin; C051928:lipoprotein-associated coagulation inhibitor; D006583:Hexadimethrine Bromide; D000990:Antithrombin III; D017985:Dalteparin