1994 Volume 9 Issue 5 Pages 675-699
The matabolic fate of NC-1300-O-3, a new proton pump inhibitor with potent cytoprotective effect on the gastric mucosa, was investigated after a single oral administration of 14C(Iz)-NC-1300-O-3 or 14C(Bz)-NC-1300-O-3 to rats and male beagle dogs.
1. The radioactivity in blood and plasma after administration of 14C(Iz)-NC-1300-O-3 to male rats at doses of 10, 30 and 100 mg/kg reached maxima within 5 hr and thereafter declined. The values of Cmax and AUC were proportional to administered doses, while the difference was observed in disappearance of radioactivity, the elimination half lives of radioactivity in the blood were prolonged compared with those in plasma. No marked differences in pharmacokinetic parameters were observed between male and female rats.
In dogs, the levels of radioactivity in the blood and plasma reached maxima at 2 hr after administration of14C(Iz)-NC-1300-O-3 at a dose of 30 mg/kg and there after declined biphasecally, and the slow elimination half-life in blood radioactivity, but less compared to rats, was also observed.
When the 14C(Bz)-NC-1300-O-3 was administered to male rats, the levels of radioactivity in the blood and plasma were 2-7 times lower than those following 14C(Iz)-NC-1300-O-3 administration at the same dose level. However there was almost no difference between the pharmacokinetic parameters derived from the blood and plasma.
2. High levels of radioactivity were observed in the liver, kidney and gastrointestinal tracts after administration of 14C-NC-1300-O-3 to male rats. When administered the 14C(Iz)-NC-1300-O-3, a high radioactivity in the thyroid was observed. However there was no evidence of an accumulation of radioactivity, excluding blood.
3. The protein binding of 14C(Iz)-NC-1300-O-3 in vitro was more than 98.8% in rat, dog and human plasma. The binding of radioactive substances tc plasma proteins after oral administration of 14C-NC-1300-O-3 was 72.8-87.4% in rats, 61.7-77.5% in dogs, respectively.
4. The ratio of blood to plasma concentration after addition of 14C-NC-1300-O-3 to rat blood was increased with time, but almost no changes were observed in the blood of dog, monkey and human.
5. Within 168 hr after oral administration of 14C(Iz)-NC-1300-O-3 to male rats, 69.7 and 26.8% of the dose were excreted into urine and feces, respectively. On the other hand, 30.6 and 67.7% of the dose were excreted into urine and feces in case of 14C (Bz)-NC-1300-O-3. After administration of 14C(Iz)-NC-1300-O-3 and 14C(Bz) -NC-1300-O-3 to bile duct-cannulated male rats, 41.1 and 77.0% of the dose were excreted to bile within 48 hr, respectively, and approximately 80% of excreted radioactivity to bile was reabsorbed by entero-hepatic circulation.
In dogs, the main excretion route was feces, 64.0 or 91.2% of the dose was excreted into feces within 168 hr after administration of 14C(Iz)-NC-1300-O-3 or 14C(Bz)-NC-1300-O-3.
