Abstract
1. Differences in receptor-mediated endocytosis kinetics between pamiteplase, an engineered t-PA, and an unmodified rt-PA were examined using liver cell plasma membranes and isolated rat hepatocytes. 2. Whereas the binding site of pamiteplase on hepatocytes was the same as that of rtPA, the Kd of pamiteplase was 5.1-7.7 times larger than that of rt-PA, indicating a lower affinity of pamiteplase for the t-PA receptor. 3. ke for pamiteplase measured using parenchymal cells or non-parenchymal cells was slightly smaller than that for rt-PA, whereas k on for pamiteplase were much lower than that of rt-PA, suggesting that the interaction between pamiteplase and the receptor is slower than that of rt-PA because of its structural modification. 4. Therefore, the difference in drug disposition between pamiteplase and rt-PA is mainly due to the difference in the hepatic clearance caused by a change in the interaction rate between the ligand and its cell-surface receptor.