Abstract
The absorption, excretion and metabolism of S-1108, an ester-type prodrug of S-1006, have been examined in rats and dogs by administering 14C-labeled S-1108 or S-1006 in a dose of 20 mg/kg.
In non-fasted rats, the plasma concentration of radioactivity after oral administration of [7-14C]-S-1108 reached a maximum of 2.4 μg equiv./ml 30 min after administration, then decreased with a half-life of 0.8 h until 4 h. The AUC was 7.09 μg equiv.·h/ml. The same maximum concentration time, but lower maximum concentration, 1.7 μg equiv./ml, and smaller AUC, 5.12μg equiv.·h/ml, were obtained in fasted rats.
After oral administration of [7-14C]-S-1108, 28.1% and 70.8% of th radioactivity was excreted in the urine and feces, respectively, of non-fasted rats, while the corresponding values in fasted rats were 18.4% and 80.5%. Biliary excretion in fasted bile duct-cannulated rats was 7. 8%. The calculated absorption ratio was 40% in non-fasted rats and 25% in fasted rats.
Urinary and biliary metabolites in rats were examined by TLC-autoradiography, and it was concluded that hardly any biotransformation of 5-1006 occurred. The plasma concentration of radioactivity after oral administration of [7-14C]-S-1108 to fasted dogs reached a maximum of 5.76 μg equiv./ml 1-1.5 h after administration, then declined with a halflife of 17 h. The AUC was 33.0μg equiv.·h/ml. Excretion of radioactivity at this dose was 25.3% in the urine and 70.2% in the feces up to 24 h after administration. When [7-14C]-S-1108 was administered at 400 mg/kg reduction of the absorption ratio was observed.
Serum protein binding of [7-14C]-S-1006 in vitro was rather low in all animal species examined and in man, and in vivo binding after oral administration of [7-14C]-S-1108 to rats and dogs was also low.
