Abstract
The hemoglobin vesicle (HbV) is an artificial oxygen carrier that encapsulates a concentrated Hb solution in lipid vesicles (liposomes). The pharmacokinetic properties of HbV were investigated in mice and rats. With use of HbV in which the internal Hb was labeled with 125I (125I-HbV) and cell-free 125I-Hb, it was found that encapsulation of Hb increased the half-life by 30 times, accompanied by decreased distribution in both the liver and kidney. The half-life of HbV was increased, and the uptake clearance for the liver and spleen were decreased with increasing doses of HbV. In an in vitro study, the specific uptake and degradation of HbV in RAW 264.7 cells were found, but this was not the case for parenchymal and endothelial cells. The pharmacokinetics of HbV components (internal Hb and liposomal lipid) were also investigated using 125I-HbV and 3H-HbV (liposomal cholesterol was radiolabeled with tritium-3). The time courses for the plasma concentration curves of 125I-HbV, 3H-HbV, and iron derived from HbV suggest that HbV maintain an intact structure in the blood circulation up to 24 h after injection. 125I-HbV and 3H-HbV were distributed mainly to the liver and spleen. Internal Hb disappeared from both the liver and spleen 5 days after injection, and the liposomal cholesterol disappeared at approximately 14 days. Internal Hb was excreted into the urine and cholesterol into feces via biliary excretion. These results suggest that the HbV has a reasonable blood retention and metabolic and excretion performance and could be used as an oxygen carrier.
Footnotes
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This work was supported in part by the Ministry of Health, Labour and Welfare, Japan [Health Science Research Grants (Health Science Research Including Drug Innovation)].
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K.T. and Y.U. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027094.
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ABBREVIATIONS: RBC, red blood cell; HbV, hemoglobin vesicle(s); PEG, polyethylene glycol; NO, nitric oxide; 125I-HbV, 125I-labeled hemoglobin vesicle; 3H-HbV, 3H-labeled hemoglobin vesicle; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine; rHSA, recombinant human serum albumin; BSA, bovine serum albumin; TCA, trichloroacetic acid; PBS, phosphate-buffered saline; WE, Williams' E medium; FCS, fetal calf serum; AUC, area under the concentration-time curve; MPS, mononuclear phagocyte system; ID, injected dose; Hp, haptoglobin; CLuptake, uptake clearance.
- Accepted April 9, 2009.
- Received February 11, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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