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Pharmacokinetic Study of Enclosed Hemoglobin and Outer Lipid Component after the Administration of Hemoglobin Vesicles as an Artificial Oxygen Carrier

Department of Biopharmaceutics (K.T., Y.U., M.A., T.M., H.W., M.O.), Center for Clinical Pharmaceutical Sciences (T.M., H.W.), and Department of Medical Biopolymer (T.K.), Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Research Institute for Science and Engineering, Waseda University, Tokyo, Japan (H.S., E.T.); Department of Surgery, School of Medicine, Keio University, Tokyo, Japan (K.K., H.H.); and Pharmaceutical Research Center, Nipro Corporation, Shiga, Japan (T.K.)

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.

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				K. Taguchi, Y. Urata, M. Anraku, H. Watanabe, D. Kadowaki, H. Sakai, H. Horinouchi, K. Kobayashi, E. Tsuchida, T. Maruyama, et al. Hemoglobin Vesicles, Polyethylene Glycol (PEG)ylated Liposomes Developed as a Red Blood Cell Substitute, Do Not Induce the Accelerated Blood Clearance Phenomenon in Mice Drug Metab. Dispos., November 1, 2009; 37(11): 2197 - 2203. [Abstract] [Full Text] [PDF]