Pharmacokinetics and metabolism of radiolabelled SNI-2011, a novel muscarinic receptor agonist, in healthy volunteers. Comprehensive understanding of absorption, metabolism and excretion using radiolabelled SNI-2011.
The pharmacokinetics and metabolism of SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sjögen's syndrome, were investigated in six healthy volunteers after a single oral administration of 14C-SNI-2011. After administration, plasma concentrations of the radioactivity and SNI-2011 reached to Cmax at approximately 2 h, and then decreased with t 1/2 of 9 and 4 h, respectively. Cmax and AUC0-infinity of the radioactivity in plasma were 2.2 and 5.0 times higher than those of SNI-2011, respectively. The main excretion route of the radioactivity was urine, and 97.3% of the dose excreted in urine within 168 h, indicating that 14C-SNI-2011 was completely absorbed. The mean recoveries of the metabolites in urine at 24 h after administration were 16.0% for SNI-2011, 35.8% for SNI-2011 trans-sulfoxide (SNI-t-SO), 8.7% for SNI-2011 cis-sulfoxide, 4.1% for SNI-2011 N-oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6% and 7.7%, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of SNI-2011 and SNI-t-SO, respectively.
Washio
Takuo
T
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd, Tochigi, Japan. washio-t-e@pop16.odn.ne.jp
Kohsaka
Kazuhiro
K
Arisawa
Hirohiko
H
Masunaga
Hiroaki
H
Nagatsuka
Shin-ichiro
S
Satoh
Yoshiaki
Y
D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007553:Isotope Labeling; D008297:Male; D013058:Mass Spectrometry; D018721:Muscarinic Agonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011812:Quinuclidines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D013876:Thiophenes
D018721:Muscarinic Agonists; D011812:Quinuclidines; D013876:Thiophenes; C059240:cevimeline