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

We investigated the plasma concentration profile, distribution, metabolism and excretion of radioactivity after a single intravenous administration of 125I-YM866 in male rats. 1. After a single intravenous administration of 125I-YM866, more than 50% of this drug rapidly formed two high molecular complexes with plasma proteins. The ratio of trichloroacetic acid (TCA)-precipitable radioactivity to total radioactivity in plasma decreased with time, suggesting that this drug is metabolized into low molecular weight metabolite or free 125I. Immunoreactive YM866 concentrations decreased more rapidly than total or TCA-precipitable radioactivity. 2. After a single intravenous adminis tration of 125I-YM866, radioactivity levels were highest in the plasma, followed by whole blood, liver, kidney, adrenal gland, spleen, lung, pituitary gland and thyroid. Radioactivity levels in these tissues were one-quarter or half of that in the plasma, and the level in the brain was much lower than in the plasma. Except for the uptake of the released 125I by some specific tissues, the radioactivity in most tissues decreased rapidly. Although most of the radioactivity in tissues were precipitable with TCA at an early stage after administration, the ratio of TCA-precipitate to total radioacivity decreased rapidly with time. 3. After a single intr avenous administration of 125I-YM866, 91.2% and 3.9% of the dosed radioactivity was excreted in urine and feces within 144 hr, respectively. Most of the radioactivity in urine was not precipitable with TCA and eluted in the gel filtration chromatographic (GFC) analysis at a low molecular region, suggesting that the radioactivity was excreted as low molecular weight materials 4. The concentration of 125I-YM866 in plasma was higher than that of 125I-tissue plasminogen activator (125I-t-PA), probably because 125I-YM866 was distributed less extensively to the liver than 125I-t-PA.