Pharmacokinetics of full length and two-domain tissue factor pathway inhibitor in combination with heparin in rabbits.
Tissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus. FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg). Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.
Bregengaard
C
C
Novo Nordisk A/S, Gentofte, Denmark.
Nordfang
O
O
Ostergaard
P
P
Petersen
J G
JG
Meyn
G
G
Diness
V
V
Svendsen
O
O
Hedner
U
U
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005246:Feedback; D006493:Heparin / Q000494:pharmacology*; D008074:Lipoproteins / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D017434:Protein Structure, Tertiary; D011817:Rabbits
D000925:Anticoagulants; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin