Absorption , Excretion and Metabolism of 14 C-SNI-2011 in Dogs

Pharmacokinetics of SNI-2011 (2): Absorption, Excretion and Metabolism of 14C-SNI-2011 in Dogs Takashi KAWASHIRO, Yayoi SHIMIZU, Takashi NOGAMI, Kouwa YAMASHITA, Takuo WASHIO* , Kazuhiro KOHSAKA*, tsushi TAKAO**, Hiroki EBINE**, Kazue NEMOT0** and Shuichiro TSUTSUMI** Research & Development Division, Pharmaceuticals Group , Nippon Kayaku Co., Ltd., Tokyo; *Research Institute of Life Science , Snow Brand Milk Products Co., Ltd., Tochigi; **ADME/TOX Research Institute , Daiichi Pure Chemicals Co., Ltd., Ibaraki Summary: The absorption, excretion and metabolism of SNI-2011, a novel muscarinic acetylcholine r cep tor agonist developed as an agent improving the symptoms of dry mouth or dry eye caused by Sjogren's yn drome, were studied in dogs. 1. After a single oraladministration f14C-SNI-2011 to male dogs, blood and plasma level of radioactivity reached the maximum at approximately 1 hour, and declined by the bi-exponential manner . Blood and plasma half-lives of radioactivity ina phase were similar, however, blood half-life in /3 phase was longer than that ob served in plasma. The distribution of radioactivity inblood cell was 27-54% up to 8 hours, and then increased with time reaching the values of more than 80% at 24 hours. 2. Cumulative xcretion rates of radioactivity in urine and feces were approximately 95% and 0.7%, respectively, within 168 hours after administration, indicating that the main elimination route is the urinary tract. 3. Plasma concentrations ofSNI-2011 N-oxide (SNI-NO) were 32 and 23 times higher in male and female dogs, respectively, than those of unchanged form. Main metabolite found in dog's urine was also SNI-NO. 4. There was no sex-related ifference in blood and plasma concentration, excretion and metabolism of SNI-2011 in dogs after a single oral administration.