Studies on the Metabolic Fate of M17055, a Novel Diuretic. (1): Plasma Concentration and Excretion of Radioactivity in Rat and Dog after a Single Intravenous Administration of [14C]M17055

The plasma level and excretion of radioactivity were studied following a single intravenous administration of [14C]M17055 to male and female rats, and a female dog. 1. After a single intravenous administration to male and female rats at a dose of 0.3 mg/kg, plasma levels of radioactivity declined triphasically reaching at 48 hr the levels lower than 1/1000 of those observed at one minute after administration. Calculated CLtot, T1/2βand T1/2γ did not differ between male and female rats. But T1/2α of female rats showed lower value than that of male rats. 2. After a single intravenous administration to male rats at doses of 0.1, 1 and 3 mg/kg, plasma levels of radioactivity declined in similar manner with that at a dose of 0.3 mg/kg. Although calculated CLtot tends to decline at 1 and 3 mg/kg, the T1/2γ showed similar value at the dose range of 0.1-3 mg/kg. 3. Plasma level of radioactivity in a female dog declined triphasically reaching at 48 hr the levels 100 fold lower than those observed at 5 minutes after a single intravenous administration at a dose of 1 mg/kg. There-after, the level of radioactivity declined more slowly when compared with rats. 4. Cumulative urinary and fecal excretions of radioactivity within 168 ho urs after a single intravenous administration to male and female rats accounted for 94.10 and 97.61% of the dose, respectively. Over 90% of the dose was excreted within 48 hours after administration. Urinary excretion rate was higher in female rats than that in male rats, especially within 6 hours after administration. 5. Cumulative urinary and fecal excretions after a single intravenous administration to a female dog accounted for over 90% after administration. Total excretion of radioactivity within 168 hours accounted for 97.33% of the administered dose. 6. Biliary excretion of radioactivity after a single intravenous administration to bile-duct cannulated male rats accounted for 64.12% of the dose. About 67% of the excreted radioactivity in bile was re-absorbed in male rats. 7. The renal clearance of radioactivity after administration in male and female rats decreased and showed same level when treated with probenecid, which suggested that the sex difference of the urinary excretion may be caused by the active secretary mechanism.