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

作者：Taguchi Kazuaki; Miyasato Mayumi; Watanabe Hiroshi; Sakai Hiromi; Tsuchida Eishun; Horinouchi Hirohisa; Kobayashi Koichi; Maruyama Toru; Otagiri Masaki^*

来源：Journal of Pharmaceutical Sciences, 2011, 100(2): 775-783.

DOI：10.1002/jps.22286

• pharmacokinetics
• hepatocyte
• biliary excretion
• metabolism
• liposomes

The hemoglobin-vesicle (HbV) is a cellular, hemoglobin-based oxygen carrier. Our previous pharmacokinetic studies demonstrated that the liver is strongly associated with the metabolism and excretion of HbV. The aim of this study was to evaluate the pharmacokinetics of HbV in a chronic cirrhosis rat (CCR) model induced by carbon tetrachloride (CCl(4)) and explore whether liver functional parameters and Kupffer cell (KC) phagocyte activity are related to the pharmacokinetics of HbV. The CCRs were induced three times weekly by intraperitoneal administration of CCl(4) for 8 weeks and categorized as Child-Pugh grade B. To analyze the pharmacokinetics, the CCRs were given a single intravenous injection of (3)H-HbV (1400 mg of Hb/kg). The total clearance and hepatic distribution of HbV were negatively correlated with plasma aspartate aminotransferase (AST) levels (p = 0.007). In addition, the phagocyte index was negatively correlated with plasma AST levels (p = 0.047). The excretion of lipid components in feces was also negatively correlated with plasma AST levels (p = 0.049). In conclusion, alteration in the pharmacokinetics of HbV in CCRs can be attributed to a decrease in KC phagocyte activity and the extent of damage to parenchymal cells. This represents the first demonstration of the pharmacokinetics of a liposome preparation in chronic liver impairment.

• 出版日期2011-2