Recombinant human serum albumin dimer has high blood circulation activity and low vascular permeability in comparison with native human serum albumin.
OBJECTIVE
Human serum albumin (HSA) is used clinically as an important plasma expander. Albumin infusion is not recommended for critically ill patients with hypovolemia, burns, or hypoalbuminemia because of the increased leakage of albumin into the extravascular spaces, thereby worsening edema. In the present study, we attempted to overcome this problem by producing a recombinant HSA (rHSA) dimer with decreased vascular permeability and an increased half-life.


METHODS
Two molecules of rHSA were genetically fused to produce a recombinant albumin dimer molecule. The pharmacokinetics and biodistribution of the recombinant proteins were evaluated in normal rats and carrageenin-induced paw edema mouse model.


RESULTS
The conformational properties of this rHSA dimer were similar to those for the native HSA (the HSA monomer), as evidenced by the Western blot and spectroscopic studies. The biological half-life and area under the plasma concentration-time curve of the rHSA dimer were approximately 1.5 times greater than those of the monomer. Dimerization has also caused a significant decrease in the total body clearance and distribution volume at the steady state of the native HSA. rHSA dimer accumulated to a lesser extent in the liver, skin, muscle, and fat, as compared with the native HSA. Up to 96 h, the vascular permeability of the rHSA dimer was less than that of the native HSA in paw edema mouse models. A prolonged plasma half-life of the rHSA dimer was also observed in the edema model rats.


CONCLUSIONS
rHSA dimer has a high retention rate in circulating blood and a lower vascular permeability than that of the native HSA.
Matsushita
Sadaharu
S
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Chuang
Victor Tuan Giam
VT
Kanazawa
Masanori
M
Tanase
Sumio
S
Kawai
Keiichi
K
Maruyama
Toru
T
Suenaga
Ayaka
A
Otagiri
Masaki
M
D000818:Animals; D002199:Capillary Permeability; D002351:Carrageenan; D003001:Cloning, Molecular; D019281:Dimerization; D004487:Edema / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D010952:Plasma Substitutes / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000737:chemistry / Q000493:pharmacokinetics*
D010952:Plasma Substitutes; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D002351:Carrageenan