N' ALKYLAMINE LOW-MOLECULAR-MASS HEPARINS (LMM-HEPARIN-TYRAMINE AND LMM-HEPARIN-TYRAMINE-FITC) EXHIBIT LONG-LASTING ANTICOAGULANT EFFECTS

The pharmacodynamic and pharmacokinetic properties of endpoint-attache d N'alkylamine derivatives of low molecular mass heparin (LMMH), low m olecular mass heparin-tyramine (LMMH-tyr) and low molecular mass hepar in-tyramine-fluorescein-5-isothiocyanate (LMMH-tyr-fitc) were investig ated ex vivo. After intravenous bolus injection of LMMH, LMMH-tyr and LMMH-tyr-fitc (150 aXa U/kg) to Sprague-Dawley rats (n = 8), LMMH-tyr and LMMH-tyr-fitc displayed decreased clearances. The beta-half-life t ime of the antifactor Xa (aXa) of ''endpoint-attached heparins'' was s ignificantly prolonged: LMMH-tyr (125 min), LMMH-tyr-fitc (141 min) co mpared to LMMH (69 min). The pharmacokinetics of LMMH-tyr-fitc were me asured with reversed phase high performance liquid chromatography (RP- HPLC). It showed a decreased clearance and a prolonged half-life time (132 min). The selectively tagged LMMH-tyramine and LMMH-tyramine-fitc may be used to investigate the pharmacokinetics, plasma protein and c ellular binding of low molecular mass heparins.