TITLE

Pharmacokinetics and Metabolism of the Novel Muscarinic Receptor Agonist SNI-2011 in Rats and Dogs

AUTHOR(S)
Washio, Takuo; Kohsaka, Kazuhiro; Arisawa, Hirohiko; Masunaga, Hiroaki
PUB. DATE
January 2003
SOURCE
Drug Research / Arzneimittel-Forschung;Jan2003, Vol. 53 Issue 1, p26
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
In this study, the pharmacokinetics of SNI-2011 ((�)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydro chloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sj�gren's syndrome, in rats and dogs were determined following intravenous or oral administration using liquid chromatography/mass spectrometry (LC/MS). The in vitro metabolism of SNI-2011 was also evaluated with rat and dog liver microsomes. After oral administration, plasma concentrations of SNI-2011 reached to C[SUBmax] within 1 h in both species, suggesting that SNI-2011 was quickly absorbed, and then decreased with a t[SUB1/2] (of 0.4)-1.1 h. The bioavailability was approximately 50 % and 30 % in rats and dogs, respectively. Major metabolites in plasma were both S- and N-oxidized metabolites in rats and only N-oxidized metabolite in dogs, indicating that a large species difference was observed in the metabolism of SNI-2011. Sex difference was also observed in the pharmacokinetics of SNI-2011 in rats, but not in dogs. In the in vitro study, chemical inhibition and pH-dependent studies revealed that the sulf-oxidation and N-oxidation of SNI-2011 were mediated by cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), respectively, in both species. In addition, CYP2D and CYP3A were mainly responsible for the sulfoxidation in rat liver microsomes.
ACCESSION #
8924005

 

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