Ito Yoshihiko, Oyunzul Luvsandorj, Yoshida Akira, Fujino Tomomi, Noguchi Yukiko, Yuyama Hironori, Ohtake Akiyoshi, Suzuki Masanori, Sasamata Masao, Matsui Minoru, Yamada Shizuo
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.
Eur J Pharmacol. 2009 Aug 1;615(1-3):201-6. doi: 10.1016/j.ejphar.2009.04.068. Epub 2009 May 13.
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.
索利那新是一种新型的M(3)毒蕈碱受体选择性拮抗剂，用于治疗膀胱过度活动症。本研究旨在通过使用毒蕈碱受体亚型敲除(KO)小鼠来表征索利那新在膀胱和颌下腺中的体内毒蕈碱受体亚型选择性。通过使用[N-甲基-(3)H]东莨菪碱([(3)H]NMS)的放射性配体结合测定法，测量野生型、M(2)R KO和M(3)R KO小鼠在体外以及口服索利那新和奥昔布宁后的膀胱和颌下腺中的毒蕈碱受体。在体外，奥昔布宁和索利那新在M(2)R KO小鼠的膀胱和颌下腺中的受体结合活性几乎没有差异，表明这两种组织对残留的(主要是M(3)亚型)毒蕈碱受体具有相同的亲和力。相比之下，与口服奥昔布宁相比，口服索利那新在M(2)R KO小鼠的膀胱中与毒蕈碱受体结合的活性明显更高，而在颌下腺中与毒蕈碱受体结合的活性明显更低。在M(3)R KO小鼠的膀胱和颌下腺中，索利那新和奥昔布宁的结合活性没有显著差异。野生型、M(2)R KO和M(3)R KO小鼠口服后索利那新和奥昔布宁的血浆浓度差异不大。结果表明，与口服奥昔布宁不同，口服索利那新在体内与颌下腺中的此类受体相比，可能选择性地与膀胱中的毒蕈碱M(3)亚型结合。就对膀胱中M(3)受体的高亲和力而言，口服索利那新可能有利于治疗膀胱过度活动症。
