Metabolic fate of recombinant human tissue plasminogen activator(rt-PA). (2): Blood or plasma concentration, distribution, metabolism, excretion and accumulation in rats after repeated intravenous administration.

Abstract

Blood or plasma concentration, distribution, metabolism, excretion and accumulation of rt-PA were investigated in male rats after repeated intravenous administration of 125I-rt-PA for 15 days. 1. During the repeated intravenous administration of 125I-rt-PA, blood or plasma total radioactivity, radioactivity in TCA precipitate, immunoreactive rt-PA, fibrinolytic activity, unchanged rt-PA and its metabolites were constant at 5 min after each dosing. After the repeated intravenous administration of 125I-rt-PA for15 days, blood or plasma total radioactivity and radioactivity in TCA precipitate decreased slower than those after single administration, but decline of the immunoreactive rt-PA level and fibrinolytic activity were same as those after single administration. 2. During the repeated intravenous administration of 125I-rt-PA, the radioactivity in organs at 24 hr after each dosing increased gradually till 5 th or 10 th days and remained almost constant till 15 th day. After repeated intravenous administration of 125I-rt-PA for 15 days, the total radioactivity and radioactivity in TCA precipitate in each organ decreased slowly than those after single administration. At 5 min after each dosing, immunoreactive rt-PA levels in the liver and kidney were unchanged during the repeated administration. There was no clear indication of accumulation of rt-PA. 3. The excretion of radioactivity in the urine and feces was nearly the same throughout the period of repeated intravenous administration of 125I-rt-PA. Within 120 hr after the last dosing, 90 % and 8 % of the administered radioactivity excreted into the urine and feces, respectively.