Development of drug delivery systems for cytokines with an aim of efficient exertion of their pharmacological effect

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In this year, we atte mpted to clarify the elimination mechanism of hepatocyte growth factor (HGF), which is expected to be developed as a treatment for certain types of liver diseases, and to develop its drug delivery system considering its elimination mechanism. In addition, we also investigated the clearance mechanism for granulocyte-colony stimulating factor (G-CSF) analog, which is now developed as a treatment for bone suppression during cancer chemotherapy. To characterize the clearance mechanism of HGF,we examined its pharmacokinetics in rats after partial hepatectomy. Based on the findings in both in vivo and perfused liver system, we demonstrate that both receptor-mediated endocytosis and the other nonspecific uptake mechanism in the liver contribute to the over all disposition of HGF.Furthermore, in the liver-diseased conditions such as partial hepatectomy, HGF clearance via the former mechanism is dramatically downregulated while that via the latter mechanism is maintained a … More t the normal level (K.Liu et al.Am.j.Physiol., 269 : G1-G9,1995). The latter clearance mechanism, which is presumably the uptake of HGF by cell-surface heparin-like substance, is found out not only a the liver parenchymal cells (hepatocytes), but also at the non-parenchymal cells. The nonspecific uptake at the non-parenchymal cells contributs to the HGF disposition especially at the higher dose, which results in the pharmacological action of HGF (Ke-Xin Liu et al.Pharm.Res.12 : 1737-1740,1995). To suppress such a nonspecific elimination, HGF was incubated with heparin to form heparin-HGF complex, and subsequently administered into the ANIT-treated rats. Several marker enzyme levels for the livery injury (such as GOT,GPT,ALP,and LAP) were dramatically decreased after the administration of such heparin-HGF complex, compared with those values after the administration of HGF alone. Plasma clearance of HGF after the injection of complex was much lower than that after the injection of HGF alone, suggesting that this heparin-HGF complex can be a candidate for the drug delivery system for HGF (In preparation for submission to journal). However, stimulation of DNA synthesis in the liver, assessed by the labeling index technique, was comparable between for the heparin-HGF complex and HGF alone, implying that further studies are required for the adequate drug delivery system for HGF.Based on the pharmacokinetic analysis of the G-CSF analog, we found out that not the liver nor the kidney, but the bone marrow is the major clearance organ for G-CSF analog (T.Kuwabara et al.Am.J.Physiol., 269 : E1-E9,1995 ; T.Kuwabara et al.J.Pharmacol.Exp.Ther., 273 : 1114-1122,1995). Less