title: Comparison of muscarinic receptor selectivity of solifenacin and oxybutynin in the bladder and submandibular gland of muscarinic receptor knockout mice.
abstract: Solifenacin is a novel selective antagonist of M(3) muscarinic receptor developed for the treatment of overactive bladder. The current study was undertaken to characterize in vivo muscarinic receptor subtype selectivity of solifenacin in the bladder and submandibular gland by using muscarinic receptor subtype knockout (KO) mice. Muscarinic receptors in the bladder and submandibular gland of wild type, M(2)R KO and M(3)R KO mice under in vitro and after oral administration of solifenacin and oxybutynin were measured by radioligand binding assay using [N-methyl-(3)H]scopolamine ([(3)H]NMS). There was little difference between the bladder and submandibular gland of M(2)R KO mice in the receptor binding activities of oxybutynin and solifenacin in vitro, suggesting equal affinity for residual (predominantly M(3) subtype) muscarinic receptors in both tissues. In contrast, compared with oral oxybutynin, oral administration of solifenacin exerted a significantly greater activity to bind muscarinic receptors in the bladder of M(2)R KO mice, while exhibiting a significantly less activity to bind those in the submandibular gland. In the bladder and submandibular gland of M(3)R KO mice, the binding activity of solifenacin and oxybutynin showed no significant difference. Plasma concentrations of solifenacin and oxybutynin after oral administration differed little among wild type, M(2)R KO and M(3)R KO mice. The results indicate that oral solifenacin, unlike oral oxybutynin, may selectively bind to the muscarinic M(3) subtype in the bladder compared with such receptors in the submandibular gland in vivo. Oral solifenacin may be advantageous for the treatment of overactive bladder, in terms of high affinity for M(3) receptors in the bladder.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Luvsandorj
authors.initials: L
authors.lastname: Oyunzul
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujino
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Yuyama
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ohtake
authors.forename: Masanori
authors.initials: M
authors.lastname: Suzuki
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsui
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D008333:Mandelic Acids / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018727:Muscarinic Antagonists / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding; D011812:Quinuclidines / Q000097:blood / Q000494:pharmacology*; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D000069464:Solifenacin Succinate; D013363:Submandibular Gland / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000494:pharmacology*; D001743:Urinary Bladder / Q000378:metabolism*
chemical_list: D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D044005:Tetrahydroisoquinolines; C005419:oxybutynin; D000069464:Solifenacin Succinate