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

（1）大鼠枯否细胞、原代培养肝实质细胞和腹腔巨噬细胞对高分子量肝素（20，000 Da）的摄取呈浓度依赖性。Kupffer细胞和腹腔巨噬细胞的解离常数K_d相似，分别为5.7和6.7 nM，而肝实质细胞的解离常数K_d远低于53.5 nM。Kupffer细胞和腹腔巨噬细胞的最大结合容量B_<max>分别为1.5和1.9 pmol/10^6细胞。而肝实质细胞则为32.8 pmol/10^6个细胞。因此，与枯否细胞和腹腔巨噬细胞相比，肝实质细胞对分级肝素具有更大的结合能力和更低的亲和力。（2）原代培养的枯否细胞和肝实质细胞的解离常数K_d随肝素分子量的减小而增大，而最大结合容量B_<max>d基本不变。（3）[^3 H]肝素的表观释放常数K_&lt;rel，app&gt;为表观内化常数K_&lt;int，app&gt;的1/3，并随温度从37 ℃降至4 ℃而降低。（4）当分级[^3H]肝素的内标量从0.259 pmol/mg蛋白增加到5.764 pmol/mg蛋白时，内标分级[^3H]肝素的表观释放常数K_（rel，app）从0.074 h_（？<-1>）另一方面，表观释放常数不受添加α-球蛋白，氯喹或莫能菌素的孵育介质。

(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.