Metabolic Fate of a New 5-HT₃ Receptor Antagonist, Y-25130 (I): Plasma Concentration, Distribution, Metabolism and Excretion of ¹⁴C-Y-25130 after Intravenous Administration to Rats

Abstract

The plasma concentration, distribution, metabolism and excretion of ¹⁴C-Y-25130 were investigated in rats after intravenous administration.
1. Plasma levels of radioactivity (¹⁴C) decreased multiexponentially at the dose levels of 0.4, 1, 2, 10mg/kg, and the terminal half-lives (t_1/2z) were 8.4 -9.5 hours. No dose or sex differences in t_1/2z were observed. The areas under the plasma level-time curve were approximately proportional to the dose. Tissue levels of ¹⁴C were high in the liver, lung, kidney, pituitary gland, submaxillary gland, pancreas, stomach, adrenal, bone marrow, thyroid and spleen. Radioactivity rapidly disappeared from all tissues and was not detected in carcasses 96 hours after administration, suggesting no accumulation of ¹⁴C.
2. Binding rates of ¹⁴C to plasma proteins were 42.8-44.6% during 0.25-2 hours after administration.
3. Four days after administration to male rats at a dose of 1 mg/kg, urinary and fecal excretion of ¹⁴C were 45.5% and 52.9% of administered dose, respectively. At this dose, urinary excretion was much higher in female rats than in male rats. The excretion in male rats increased significantly at the highest dose level. Unchanged drug was found mainly in urine, while the unchanged drug, M1 and M3 were present in feces. The amount of unchanged drug in urine was much higher in female rats than in male rats. This amount increased at the highest dose level in male rats.
4. Fourty eight hours after administration to bile-duct cannulated male rats, 42.0% of the dose was excreted in bile and 12.8% in feces. This result indicates that another direct excretion route to the gastrointestinal tract exist besides the bile. About 13% of ¹⁴C excreted in bile was reabsorbed from the intestines by the enterohepatic circulation.