Studies on the Metabolic Fate of Modified Recombinant Tissu-Type Plasminogen Activator (E6010) (2): Blood or Plasma Concentration, Distribution, Metabolism and Excretion in Rats after Repeated Intravenous Administration of 125I-E6010.

Abstract

Blood or plasma concentration, distribution, metabolism and excretion of E6010 were studied in male rats during and after repeated daily intravenous administration of 0.4 mg/kg of 125I-E6010 for 10 days. 1. At 5 min after the repeated intravenous administration of 125I-E6010 for 10 days, blood or plasma levels of total and TCA-precipitable radioactivity, immunoreactive E6010 and the unchanged E6010 and its metabolites were the same as those at 5 min after a single dosing. After the repeated intravenous administration of 125I-E6010 for 10 days, the levels of total and TCA-precipitable radioactivity in the blood or plasma decreased slower than those after a single administration, but the levels of immunoreactive E6010 and unchanged E6010 were the same as those after a single administration. 2. TCA-precipitable radioactivity level at 24 hr afte r the last dosing in most tissues did not exceed the levels after a single dose by 3 times, except in spleen (3.7 times), bone marrow (3.7 times) and thyroid (3.2 times). After repeated intravenous administration of 125I-E6010, the levels of total and TCA-precipitable radioactivity in each tissue decreased slower than those after a single dosing, but the levels of the immunoreactive E6010 in the liver and kidney were the same as those after a single dosing. 3. The excretion of radioactivity in the urine and feces was nearly the same th roughout the period of repeated intravenous administration of 125I-E6010. Within 7 days after the last dosing, 92.42% and 7.74% of the administered radioactivity was excreted into the urine and feces, respectively. Radioactivity excreted in the urine after the last dosing consisted almost of small molecular weight metabolites or free 125I, similar to that after a single administration.