Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs.
Article Details
- CitationCopy to clipboard
Washio T, Kohsaka K, Arisawa H, Masunaga H
Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs.
Arzneimittelforschung. 2003;53(1):26-33.
- PubMed ID
- 12608011 [ View in PubMed]
- Abstract
In this study, the pharmacokinetics 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 Sjogren'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 Cmax within 1 h in both species, suggesting that SNI-2011 was quickly absorbed, and then decreased with a t1/2 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Cevimeline Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Cevimeline Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Cevimeline Dimethylaniline monooxygenase [N-oxide-forming] 1 Protein Humans UnknownSubstrateDetails