Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs.
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 Sjögren'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.
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
D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D018721:Muscarinic Agonists / Q000378:metabolism / Q000493:pharmacokinetics*; D011812:Quinuclidines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012472:Salivation / Q000187:drug effects; D013876:Thiophenes; D014018:Tissue Distribution
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D011812:Quinuclidines; D013876:Thiophenes; C059240:cevimeline