title: Recombinant human serum albumin dimer has high blood circulation activity and low vascular permeability in comparison with native human serum albumin.
abstract: 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.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Sadaharu
authors.initials: S
authors.lastname: Matsushita
authors.forename: Victor Tuan Giam
authors.initials: VT
authors.lastname: Chuang
authors.forename: Masanori
authors.initials: M
authors.lastname: Kanazawa
authors.forename: Sumio
authors.initials: S
authors.lastname: Tanase
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Ayaka
authors.initials: A
authors.lastname: Suenaga
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
mesh_terms: 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*
chemical_list: D010952:Plasma Substitutes; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D002351:Carrageenan