PT  - JOURNAL ARTICLE
AU  - Taguchi, Kazuaki
AU  - Iwao, Yasunori
AU  - Watanabe, Hiroshi
AU  - Kadowaki, Daisuke
AU  - Sakai, Hiromi
AU  - Kobayashi, Koichi
AU  - Horinouchi, Hirohisa
AU  - Maruyama, Toru
AU  - Otagiri, Masaki
TI  - Repeated injection of high doses of hemoglobin encapsulated liposomes (hemoglobin-vesicles) induces accelerated blood clearance in a hemorrhagic shock rat model
AID  - 10.1124/dmd.110.036913
DP  - 2010 Dec 01
TA  - Drug Metabolism and Disposition
PG  - dmd.110.036913
4099  - http://dmd.aspetjournals.org/content/early/2010/12/01/dmd.110.036913.short
4100  - http://dmd.aspetjournals.org/content/early/2010/12/01/dmd.110.036913.full
AB  - 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 (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-HbV, in which the Hb inside of HbV was labeled with iodine-125. At 4 and 7 days after resuscitation from hemorrhagic shock by non-labeled HbV (1400 mg Hb/kg), the second dose of 125-HbV (1400 mg Hb/kg) was rapidly cleared from the circulation compared to normal rats. Interestingly, IgM against HbV was produced at 4 days post-first injection of HbV, but decreased at 7 days. In addition, phagocyte activity was increased at both 4 and 7 days post-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.