Metabolic Fate of YM866, a Novel Fibrinolytic Agent [II]: Plasma Concentration, Distribution, Metabolism and Excretion in Rats after Repeated Intravenous Administration

Abstract

We investigated the plasma concentration profile, distribution, metabolism and excreion of radioactivity after repeated intravenous administration of 0.3 mg/kg of ¹²⁵I-YM866 for 7 days to male rats. 1. After repeated dosing, plasma concentration-time curve profile of total and trichloroacetic acid (TCA)-precipitable radioactivity on the 7th day was closely similar to that after a single dose. In plasma, complexes of α₂-macroglobulin and α₂-plasmin inhibitor with ¹²⁵I-YM866, the unchanged YM866 and low molecular weight metabolites were observed by the gel filtration chromatographic (GFC) analysis after both single and multiple (7 days) the 7th administration.
2. Total radioactivity in tissues and corresponding tissue/plasma concentration ratios after the 7th repeated administration were closely similar to those after a single dose, except in the thyroid gland. Radioactivity distributed to the tissues rapidly disappeared from most of them. Tissue levels of radioactivity were little affected by repeated administration.
3. The excretion of radioactivity in the urine and feces showed little change throughout the period of repeated intravenous administration of ¹²⁵I-YM866. Within 120 hr after final dosing, 93.0% and 3.0% of the dosed radioactivity was excreted in urine and feces, respectively. Most radioactivity excreted in the urine was confirmed to be low molecular weight metabolites and/or free ¹²⁵I by GFC analysis.
4. These finding suggested that the metabolic fate of YM866 was little affected by repeated administration; no accumulation of radioactivity was observed.