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Recombinant Human Serum Albumin Dimer has High Blood Circulation Activity and Low Vascular Permeability in Comparison with Native Human Serum Albumin

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Purpose

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.

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Abbreviations

AUC:

area under the plasma concentration–time curve

CLtot :

total body clearance

HSA:

human serum albumin

rHSA:

recombinant HAS

Vdss :

distribution volume of the steady state

%ID:

percentage of injected dose

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Acknowledgments

We wish to thank the members of the Gene Technology Center in Kumamoto University for their important contributions to these experiments.

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Authors and Affiliations

  1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan

    Sadaharu Matsushita, Victor Tuan Giam Chuang, Masanori Kanazawa, Toru Maruyama, Ayaka Suenaga & Masaki Otagiri

  2. Department of Pharmacy, Faculty of Allied Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia

    Victor Tuan Giam Chuang

  3. Department of Analytical Biochemistry, School of Health Sciences, Kumamoto University, 4-24-1 Kuhonji, Kumamoto, 862-0976, Japan

    Sumio Tanase

  4. School of Health Sciences, Faculty of Medicine, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-1192, Japan

    Keiichi Kawai

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  1. Sadaharu Matsushita
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  2. Victor Tuan Giam Chuang
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Correspondence to Masaki Otagiri.

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Matsushita, S., Chuang, V.T.G., Kanazawa, M. et al. Recombinant Human Serum Albumin Dimer has High Blood Circulation Activity and Low Vascular Permeability in Comparison with Native Human Serum Albumin. Pharm Res 23, 882–891 (2006). https://doi.org/10.1007/s11095-006-9933-1

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