Study on Pharmacokinetics of Bioactive Macromolecular Drug for DDS : Scavenger Receptor-Mediated Internarization and Release of Fractionated [^3H] Heparin

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(1)The concentration-dependent uptake of high molecular weight fractionated heparin (20,000Da) was observed with rat Kupffer cells, liver parenchymal cells in primary culture and peritoneal macrophages. The dissociation constants, K_d for Kupffer cells and peritoneal macrophages were similar to each other showing 5.7 and 6.7 nM,respectively whereas the value for liver parenchymal cells was much lower than those showing 53.5nM.The maximum binding capacity, B_<max> were 1.5 and 1.9 pmol/10^6 cells, respectively for Kupffer cells and peritoneal macrophages, whereas liver parenchymal cells took much larger value of 32.8 pmol/10^6 cells. Thus, the liver parenchymal cells were demonstrated to have larger binding capacity and less affinity to the fractionated heparin comparing to Kupffer cells and peritoneal macrophages..(2)The dissociation constants, K_d for both Kupffer cells and liver parenchymal cells in primary culture increased with decrease of molecular weight of fractionated heparin, although the maximum binding capacity, B_<max> for both kind of cells remained almost unchanged.(3)The apparent release constant for intemalized fractionated [^3H] heparin, K_<rel, app> was one-third of the value for the apparent intemalization constant K_<int, app> and decreased when the temperature was lowered from 37ﾟC to 4ﾟC.(4)The apparent release constant for intemalized fractionated [^3H] heparin, K_<rel, app> increased from 0.074 to 0.127h^<-1>, when the intemalized amount of fractionated [^3H] heparin was raised from 0.259 to 5.764 pmol/mg protein. On the other hand, the apparent released constant was not influenced by addition of alpha-globulin, chloroquine or monensin to the incubation medium.