Abstract
Human serum albumin (HSA) is used clinically as a plasma expander in patients with hypoalbuminemia and can also function as a drug carrier. However, the administered HSA is readily eliminated from the blood circulation under pathological conditions, especially the nephrotic syndrome. In this study, we present data on the pharmacokinetics of a structurally defined HSA dimer [two HSA molecules that are cross-linked by reaction with 1,6-bis(maleimido)hexane via Cys34] in nephrotic rats and its superior circulation persistence, owing to the molecular size effect. The half-time (t1/2) of the HSA dimer persisted in the circulation 1.3 times longer than that of monomeric HSA in normal rats, primarily because of the suppression of the accumulation of the HSA dimer in the skin and muscle. In nephrotic rats, the t1/2 of the HSA monomer decreased considerably, whereas the HSA dimer remained unaltered in the blood stream, similar to that for normal rats. As a result, the t1/2 of the HSA dimer was 2-fold longer than that of the HSA monomer. This longer t1/2 can be attributed to the fact that accumulation in the kidney and urinary excretion of the HSA dimer were significantly suppressed. The cross-linked HSA dimer shows a longer blood circulation than native HSA monomer in nephrotic rats, which can be attributed to the suppression of renal filtration and leakage into the extravascular space. This HSA dimer has the potential for use as a drug carrier, new plasma expander, and an artificial albumin-based oxygen carrier under a high glomerular permeability condition such as nephrosis.
Footnotes
This research was supported in part by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science [Grant 20350058]; Grant-in-Aid for Scientific Research for Priority Area from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Area 2107); and Health Science Research Grants from the Ministry of Health, Labour, and Welfare of Japan (Regulatory Science).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.031989.
-
ABBREVIATIONS:
- HSA
- human serum albumin
- BMH
- 1,6-bis(maleimido)hexane
- 111In
- Indium-111
- PAGE
- polyacrylamide gel electrophoresis
- CD
- circular dichroism
- DTPA
- diethylenetriaminepentaacetic acid
- t1/2
- half-time
- AUC
- area under the concentration-time curve
- CL
- clearance
- Vdss
- steady-state volume of distribution
- Vd
- distribution volumes
- ID
- injection of dose
- HSA-FeP
- albumin-heme
- FcRn
- Fc receptor
- rHSA
- recombinant HSA.
- Received December 25, 2009.
- Accepted September 20, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|