title: The clearance of proteoglycan-associated human recombinant tissue factor pathway inhibitor (h-rTFPI) in rabbits: a complex formation of h-rTFPI with factor Xa promotes a clearance rate of h-rTFPI.
abstract: The very rapid clearance of human recombinant tissue factor pathway inhibitor (h-rTFPI) may result from its binding to vascular proteogly can and LDL receptor-related protein (LRP). To investigate the effect of factor Xa on the clearance of h-rTFPI, we developed a specific ELISA for h-rTFPI/factor Xa complex, and compared the pharmacokinetic parameters of h-rTFPI/factor Xa complex and the clearance rate of the cellular proteogly can-associated h-rTFPI/factor Xa complex with those of h-rTFPI by itself in rabbits. We found that the h-rTFPI/factor Xa complex disappeared from circulation at a rapid rate of clearance, having pharmacokinetic parameters similar to those of non-complexed h-rTFPI. After the rapid disappearance of the h-rTFPI complex from plasma, an intravenous injection of heparin resulted in a release of h-rTFPI/factor Xa complex into plasma. However, the recovery of heparin-releasable h-rTFPI/factor Xa decreased significantly in a time-dependent manner. Therefore, we examined the half-life of proteogly can-associated h-rTFPI/factor Xa and determined it to be 51 min, which was significantly shorter than that of h-rTFPI by itself (107 min). These results suggest that a complex formation of h-rTFPI with factor Xa promotes a clearance of proteogly can-associated h-rTFPI existing in the liver and kidney.
authors.affiliation: Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: T
authors.initials: T
authors.lastname: Hamuro
authors.forename: J
authors.initials: J
authors.lastname: Matsuda
authors.forename: S
authors.initials: S
authors.lastname: Kamei
authors.forename: K
authors.initials: K
authors.lastname: Jyu-ri
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
authors.forename: A
authors.initials: A
authors.lastname: Funatsu
authors.forename: H
authors.initials: H
authors.lastname: Kato
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015951:Factor Xa / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D005343:Fibrinolytic Agents; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D015951:Factor Xa