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

Taguchi, Kazuaki; Urata, Yukino; Anraku, Makoto; Maruyama, Toru; Watanabe, Hiroshi; Sakai, Hiromi; Horinouchi, Hirohisa; Kobayashi, Koichi; Tsuchida, Eishun; Kai, Toshiya; Otagiri, Masaki

doi:10.1124/dmd.109.027094

Cited by 57 publications

(72 citation statements)

References 37 publications

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confidence: 68%

“…[7][8][9][10] In addition, the cholesterol contained in HbV behaves similar to endogenous cholesterol after the metabolism of HbV. 9) Similar results were observed under conditions of hemorrhagic shock and chronic liver impairment. 3,11,12) Therefore, these findings strongly indicate that HbV and its components appear to show favorable metabolic and excretion profiles not only in healthy but in certain types of diseases (hemorrhagic shock and chronic liver impairment).…”

supporting

confidence: 68%

“…7,8) It has been reported that HbV are mainly captured by liver Kupffer cells and splenic macrophages in mice and rats. 8,9) Thus, the splenomegaly and hepatomegaly appear to be due to the effect of the entrapment of HbV by the mononuclear phagocyte system (MPS) in the liver and spleen.…”

Section: Resultsmentioning

confidence: 99%

“…[7][8][9][10] In addition, the cholesterol contained in HbV behaves similar to endogenous cholesterol after the metabolism of HbV.…”

Section: )mentioning

confidence: 99%

“…9) In a typical preparation, HbV (1 mL) was mixed with a [1,[2][3] H(N)]-cholesterol in ethanol (40 µL), (PerkinElmer, Inc., Yokohama, Japan) and the solution incubated for 12 h at 37°C. B6.KOR/StmSlc-Apoe shl mice (n=20) were anesthetized with ether and received a single injection of a were randomly selected at days 1, 3, 7 and 14 after the injection of 3 H-HbV, and the blood samples were collected from the inferior vena cava.…”

Section: Animalsmentioning

confidence: 99%

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Biological Responsiveness and Metabolic Performance of Liposome-Encapsulated Hemoglobin (Hemoglobin-Vesicles) in Apolipoprotein E-Deficient Mice after Massive Intravenous Injection

Taguchi

Nagao

Yamasaki

et al. 2015

Biological & Pharmaceutical Bulletin

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The hemoglobin-vesicle (HbV), a vesicle in which a concentrated human hemoglobin solution is encapsulated, was developed as an artificial oxygen carrier. Although HbV has a favorable safety, metabolic, and excretion performance in healthy animals, the effect of a massive amount of HbV, which also contains a large amount of a lipid component including cholesterol, on physiological response and metabolic performance under hyperlipidemic conditions is unclear. The aim of this study was to evaluate whether administration of HbV causes toxicity in apolipoprotein E-deficient mice (hyperlipidemic model mice). Apolipoprotein Edeficient mice were given a single injection of HbV (2000 mg hemoglobin/kg), and physiological responses and metabolic profiles were monitored for 14 d thereafter. All the mice tolerated the massive amount of HbV and survived, and adequate biocompatibility was observed. Serum biochemical parameters indicate that liver and kidney function were not remarkably affected, and morphological changes in the liver and spleen were negligible. Lipid parameters in serum were significantly increased until 3 d after HbV administration, but recovered within 7 d after the administration. In a pharmacokinetic study, HbV was mainly found distributed in the liver and spleen, and disappeared from the body within 14 d. In conclusion, even under conditions of hyperlipidemia, a massive dose of HbV and its components resulted in favorable biological compatibility, metabolic, and excretion profiles. These findings provide further support for the safety of HbV for clinical use.Key words hemoglobin; hemoglobin-vesicle (HbV); liposome; artificial blood; hyperlipidemia It is well known that liposomes (phospholipid vesicles) can be used as a carrier for some drugs, genes, proteins, and that they can enhance the blood circulation and specific targeting of encapsulated materials. Given these characteristics, many liposome type drugs have now been approved for clinical use in antifungal or anticancer therapies.1) In addition to their use in transporting drugs, phospholipid vesicles encapsulating concentrated hemoglobin (Hb), referred to as hemoglobin vesicles (HbV), have also been developed as artificial oxygen carriers. HbV has been shown to possess several superior characteristics to red blood cell (RBC) transfusions including the absence of viral contamination, a long-term storage period at room temperature of over 2 years and no need for cross-matching etc.2) Furthermore, it has been clearly shown that the transport of oxygen by HbV is comparable to RBC in hemorrhagic shock models.2,3) Based on these facts, HbV appears to have potential for use as an alternative to RBCs, and is expected to be of use in other clinical indications that cannot be solved with conventional blood transfusions in clinical settings.It is very important to accumulate data related to the overall safety of HbV because high doses of HbV, in excess of hundreds of times higher than that of other commercially available liposomal formulations of doxorubicin a...

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confidence: 68%