Biodistribution of covalent antithrombin-heparin complexes

Area of Science:

• Pharmacology
• Biochemistry
• Drug Delivery

Background:

• Covalent antithrombin-heparin (ATH) complexes offer advantages over traditional antithrombin:heparin (AT:H) mixtures, including enhanced activity and prolonged intravenous half-life.
• Reduced plasma protein binding contributes to ATH's altered pharmacokinetic profile.
• Investigating the in vivo biodistribution of ATH is crucial due to its modified clearance mechanisms.

Purpose of the Study:

• To investigate the in vivo biodistribution and systemic elimination of covalent antithrombin-heparin (ATH) complexes.
• To compare the biodistribution of ATH derived from plasma-sourced antithrombin (pATH) versus recombinant antithrombin (rhATH).
• To elucidate the role of liver uptake and degradation in the clearance of ATH.

Main Methods:

• Radiolabeled ATH (pATH and rhATH) and albumin were administered to rabbits at varying doses.
• Gamma-radioactivity was measured in tissue samples at different time points post-injection.
• Biodistribution and pharmacokinetic parameters were calculated, with vessel wall binding and urinary excretion analyzed.

Main Results:

• Recombinant human antithrombin-heparin (rhATH) exhibited significantly faster early clearance from circulation compared to plasma-derived antithrombin-heparin (pATH) at saturating doses.
• Liver-associated rhATH reached 26% +/- 3% by 20 minutes, contrasting with 3.7% +/- 0.5% for pATH.
• Over 60% of extravascular ATH was liver-associated early on, and by 24 hours, both forms were primarily found as urinary degradation products (51-63%).

Conclusions:

• The systemic elimination of ATH is substantially influenced by the source of antithrombin (plasma-derived vs. recombinant).
• Liver uptake and subsequent degradation represent a major pathway for ATH clearance.
• Understanding these biodistribution differences is critical for optimizing the therapeutic use of ATH formulations.