Disposition of KW-4679 (1) : Absorption, Distribution and Excretion of ¹⁴C-KW-4679 after Oral or Intravenous Administration to Rats

Abstract

The absorption, distribution and excretion of ¹⁴C-KW-4679 after oral or intravenous administration at a dose of 1 mg/kg were studied in male and female rats. Also the absorption and excretion of ¹⁴C-KW-4679 after oral administration at a dose of 25 mg/kg in male rats were studied.
1) ¹⁴C-KW-4679 was rapidly absorbed and the extent of absorption was estimated to be 91% or higher after oral administration of 1 mg/kg. The drug was presumably absorbed mainly in the region from the duodenum to the jejunum.
2) Plasma radioactivity reached C_max at 0.5 hr after oral administration of 1 mg/kg to fasting male rats and then disappeared biexponentially with terminal half-life of 16.8 hr. By 96 hr after administration, 42.6% and 53.5% of the administered radioactivity were excreted in urine and feces, respectively. In bile, 46.0% of radioactivity was excreted by 72 hr after administration. The excretion of radioactivity in urine, feces and bile almost completed within 24 hr after administration.
3) Delayed T_max and reduced C_max were observed after oral administration to non-fasting rats compared to fasting rats. There was no significant difference in AUC_0-∞. No difference was observed in the excretion of radioactivity in urine and feces, whether animals were fasted or not.
4) Larger AUC_0-∞ by about 18% was obtained after oral administration to female rats as compared with male rats. A tendency of lower fecal excretion and higher urinary excretion of radioactivity was demonstrated in female rats.
5) After intravenous administration of 1 mg/kg to fasting male rats, radioactivity was eliminated from plasma triexponentially with terminal half-life of 34.2 hr. By 96 hr after administration, 51.7% and 43.0%of the administered radioactivity were excreted in urine and feces, respectively.
6) Radioactivity was rapidly distributed to almost all tissues after oral administration of 1 mg/kg to fasting male rats. Except digestive organs, higher than in plasma levels of radioactivity were observed in the liver, kidney and urinary bladder. The lowest level of radioactivity was observed in the brain, where the level was about 1/25 of that in plasma, among all the organs examined. Radioactivity in tissues was eliminated almost in parallel with plasma concentration.
7) The radioactivity excreted in bile was reabsorbed (8.6%).
8) T_max, dose-normalized C_max and AUC_0-t of plasma radioactivity after oral administration at a dose of 25 mg/kg to fasting male rats was almost equal to that after oral administration at a dose of 1 mg/kg, respectively. Higher urinary excretion of radioactivity after 25 mg/kg dosing than that after 1 mg/kg dosing was observed.