2001 年 16 巻 6 号 p. 537-552
The absorption, distribution, metabolism, excretion and plasma protein binding of SNI-2011, a novel muscarinic acetylcholine receptor agonist developed as an agent improving the symptoms of dry mouth or dry eye caused by Sjögren's syndrome, were studied in rats.
1. After a single oral administration of 14C-SNI-2011 to male rats, plasma level of radioactivity reached the maximum at approximately 30 minutes, and declined by the bi-exponential manner. Oral absorption rate of radioactivity was 94%. Plasma level and pharmacokinetic parameters of radioactivity in female rats were comparable with those of male rats. 14C-SNI-2011 was considerably absorbed from duodenum, jejunum, ileum and colon. Plasma level of radioactivity at 8hr after daily oral administration of 14C-SNI-2011 increased with the number of dosing, and reached a steady state by the 3rd day.
2. After a single oral administration of 14C-SNI-2011 to male or female rats, radioactivity was distributed rapidly in whole body, and then eliminated rapidly. Tissue levels of radioactivity in male rats at 8hr after daily oral administration increased with the number of doses reaching approximately 4 times higher levels than those after the 1st administration. In pregnant rats on the 18th day of gestation, radioactivity was transferred into fetal tissues, and then decreased similarly as from maternal plasma.
3. SNI-2011 trans-sulfoxide (SNI-t-SO), SNI-2011 cis-sulfoxide (SNI-c-SO), SNI-2011 sulfone (SNI-SO2) and SNI-2011 N-oxide (SNI-NO) were identified in rat urine. As judged from the result on TLC/ radioluminography of plasma and urine samples, SNI-t-SO appeared to be the main metabolite in rats. Plasma concentration and urinary excretion rates of the unchanged SNI-2011 in female rats were higher than those in male rats. Repeated administration of SNI-2011 had no effect on liver weight, microsomal protein contents and activities of hepatic drug-metabolizing enzymes.
4. Main excretion route of 14C-SNI-2011 was urine in both of male and female rats, and approximately 100% of the dose was excreted in urine within 168 hours after administration. Fecal excretion rate of radioactivity was below 1% of the administered dose. Residual radioactivity in carcass accounted only for 0.1% of the dose. Daily urinary and fecal excretion rates of radioactivity in the period and after repeated oral administration were almost constant, and these rates were similar to those after a single administration. Radioactivity in the milk was 3.0 to 4.7 times higher than that in plasma. 5. Plasma protein binding rates of 14C-SNI-2011 in rats, dogs and human in vitro were relatively low (15.2 to 20.6%), and the binding rate was not affected by drug concentration or test species.