INVESTIGATION OF HUMAN RECOMBINANT FVIIA METABOLISM IN A PERFUSED RAT LIVER MODEL
Abstract number: P-T-054
Appa1 R., Christensen2 M.S.
11Exploratory ADME Biopharmaceuticals 22DMPK and Bioanalysis, Novo Nordisk, Maaloev, Denmark
How-to-cite Appa R, Christensen MS. INVESTIGATION OF HUMAN RECOMBINANT FVIIA METABOLISM IN A PERFUSED RAT LIVER MODEL. J Thromb Haemost 2007; 5 Supplement 2: P-T-054
Introduction: The metabolism of human recombinant activated coagulation factor VII (rFVIIa, NovoSeven®) remains largely unknown. However, tissue distribution studies (1,2) suggest that the liver may play a role. Consequently, rFVIIa metabolism was explored in perfused rat livers.
Methods: Rat livers were cannulated via the portal vein and vena cava to generate an ex vivo recirculating liver perfusion model. Samples from the perfusate and bile were collected at several timepoints and analysed for FVIIa activity and antigen concentration.
Results: The perfusion studies showed that rFVIIa uptake appears to be biphasic in the absence of plasma proteins. Approximately 35% of rFVIIa activity is cleared by the liver within the first 25 min while only an additional 10% is cleared during the remaining 95 min. A small percentage of rFVIIa was also seen in the bile supporting the existence of an active protein uptake mechanism. Further studies to understand the biphasic uptake of rFVIIa were performed. Perfusate containing rFVIIa was recirculated through one liver for 105 min, collected and then subsequently recirculated through a new liver. The resulting perfusate from the second liver was analysed for rFVIIa activity of which no significant clearance was evident. This suggests that the initial uptake is not due to distribution in the organ or possible receptor saturation. Furthermore, when additional rFVIIa was spiked after 60 min into circulating rFVIIa perfusate, a similar biphasic profile was again seen indicating the that the liver is clearing a similar population of protein.
Conclusions: Together these studies showed that in the absence of plasma proteins, the liver is active in the uptake of rFVIIa and that it may likely be due to clearance of a subpopulation of rFVIIa. The exact mechanism and relevance for in vivo liver clearance of rFVIIa is not known and warrants further investigation.
References: 1 Thomsen MK: Thromb Haemost, Vol.70(3),458-464,1993
2 Beeby TL: Thromb Haemost, Vol.70(3),465-468,1993
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
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