Alteration in the Pharmacokinetics of Hemoglobin-Vesicles in a Rat Model of Chronic Liver Cirrhosis Is Associated with Kupffer Cell Phagocyte Activity

Yamasaki

Maruyama

et al. 2017

JFB

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Hemoglobin (Hb) is an ideal material for use in the development of an oxygen carrier in view of its innate biological properties. However, the vascular retention of free Hb is too short to permit a full therapeutic effect because Hb is rapidly cleared from the kidney via glomerular filtration or from the liver via the haptogloblin-CD 163 pathway when free Hb is administered in the blood circulation. Attempts have been made to develop alternate acellular and cellular types of Hb based oxygen carriers (HBOCs), in which Hb is processed via various routes in order to regulate its pharmacokinetic properties. These HBOCs have been demonstrated to have superior pharmacokinetic properties including a longer half-life than the Hb molecule in preclinical and clinical trials. The present review summarizes and compares the pharmacokinetic properties of acellular and cellular type HBOCs that have been developed through different approaches, such as polymerization, PEGylation, cross-linking, and encapsulation.

Section: Cellular Type Hbocsmentioning

confidence: 99%

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

Yamasaki

Maruyama

et al. 2017

JFB

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“…Phagocyte activity was determined by the carbon clearance method, as described in a previous report (Sakai et al, 2001;Taguchi et al, 2010). Ten SD rats were induced with hemorrhagic shock and resuscitated with HbV, and carbon clearance was determined 4 days (n ϭ 5) or 7 days (n ϭ 5) after resuscitation.…”

Section: Methodsmentioning

confidence: 99%

“…IgM, produced in the spleen by the first injection of PEGylated liposomes, selectively binds to the second injected PEGylated liposomes and subsequent complement activation by IgM results in accelerated clearance and enhanced hepatic uptake of the second injected dose of PEGylated liposomes. In the case of HbV, there have been several explanations for the induction of the ABC phenomenon as follows: 1) HbV has a liposome structure that contains PEG; 2) our previous study, using normal mice, showed that the ABC phenomenon was not induced, but anti-HbV IgM was produced 7 days after the injection of HbV at a dose of 1400 mg Hb/kg (Taguchi et al, 2009c); and 3) the pharmacokinetic properties of HbV are altered under the various pathological conditions (Taguchi et al, 2009a(Taguchi et al, , 2010. Therefore, it is possible that the pharmacokinetics of HbV become altered by repeated administration in various pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

Iwao²,

Watanabe³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated hemoglobin solution is encapsulated in a liposome. To apply liposome preparations in clinics, it is important to consider the accelerated blood clearance phenomenon (ABC phenomenon), which involves a loss in the long-circulation half-life after being administered repeatedly to the same animals. The objective of this study was to determine whether the ABC phenomenon is induced by repeated injection of HbV under conditions of hemorrhagic shock. We created a rat model of hemorrhagic shock and performed a pharmacokinetic study using 125 I-HbV, in which the Hb inside of HbV was labeled with 125 I. At 4 and 7 days after resuscitation from hemorrhagic shock by nonlabeled HbV (1400 mg Hb/kg), the second dose of 125 I-HbV (1400 mg Hb/kg) was rapidly cleared from the circulation compared with normal rats. Of interest, IgM against HbV was produced at 4 days after the first injection of HbV, but decreased at 7 days. In addition, phagocyte activity was increased at both 4 and 7 days after the first injection of HbV. These results suggest that repeated injections of HbV at a dose of 1400 mg Hb/kg induce the ABC phenomenon under conditions of hemorrhagic shock, which is strongly related to both the production of anti-HbV IgM and enhanced phagocyte activity. We thus conclude that it might be necessary to considerer the ABC phenomenon in the dose regimen of HbV treatment in clinical settings.

“…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).…”

mentioning

confidence: 78%

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

Biological & Pharmaceutical Bulletin

Nagao

Yamasaki

et al. 2015

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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...