Hepatically-metabolized and -excreted artificial oxygen carrier, hemoglobin vesicles, can be safely used under conditions of hepatic impairment.
The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbV were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings.
Taguchi
Kazuaki
K
Department of Biopharmaceutics, Kumamoto University, 5-1 Oe-honmachi, 862-0973 Kumamoto, Japan.
Miyasato
Mayumi
M
Ujihira
Hayato
H
Watanabe
Hiroshi
H
Kadowaki
Daisuke
D
Sakai
Hiromi
H
Tsuchida
Eishun
E
Horinouchi
Hirohisa
H
Kobayashi
Koichi
K
Maruyama
Toru
T
Otagiri
Masaki
M
D000818:Animals; D001802:Blood Substitutes / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000378:metabolism* / Q000628:therapy; D006454:Hemoglobins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000008:administration & dosage / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D001802:Blood Substitutes; D006454:Hemoglobins; D008081:Liposomes; D010100:Oxygen