KINETICS OF LOW MOLECULAR WEIGHT HEPARIN IN MAN DETERMINED BY PROTAMINE CHLORIDE

Low molecular weight (LMW) heparin is characterized by a higher affinity to antithrombin HI, less inhibition of thrombin and increased inhibition of factor Xa. The half life of the antifactor Xa activity of LMW heparin is doubled compared to normal heparin. However, these parameters reflect the pharmacodynamics rather than the kinetic of the compound. We, therefore, analyzed the kinetics of LMW heparin after i.v. injection in man using protamine chloride for gravimetric evaluation of LMW heparin in the plasma samples.

Six healthy adults received 100 units per kg body weight normal heparin or 100 anti Xa units per kg LMW heparin (Sandoz AG, Niimberg, FRG). To serial samples of venous blood protamine chloride was added in serial dilutions until the thrombin inhibition was antagonized. Since factor Xa inhibition of LMW heparin cannot be abolished completely by protamine chloride, two amounts of protamine chloride were added to the plasma samples ex vivo, until factor Xa was inhibited up to 0,2 and 0,04 units/ml. The following maximal plasma concentrations (C max) and half lives (T/2) were calculated (average values):

The pharmacokinetics of normal heparin show no differences on thrombin and factor Xa interaction. LMW heparin, however, interacts to 30 % with thrombin and to 100 % with factor Xa; the half life on factor Xa is twice as long as on thrombin; releases endogenous compounds with antifactor Xa activity, which are neutralized only hardly by protamine chloride;and these endogenous compounds mediate in part the longer half life.