Comparison of in vitro selectivity profiles of solifenacin succinate (YM905) and current antimuscarinic drugs in bladder and salivary glands: a Ca2+ mobilization study in monkey cells.
We investigated the effects of the new muscarinic receptor antagonist solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] and the current antimuscarinic drugs for the treatment of overactive bladder (oxybutynin, tolterodine and darifenacin) on intracellular Ca(2+) mobilization in response to M(3) muscarinic receptor activation in bladder smooth muscle and submandibular gland cells isolated from Cynomolgus monkeys. Solifenacin concentration-dependently inhibited carbachol-induced Ca(2+) mobilization, with affinity constant values (pKi) of 8.5 +/- 0.053 in bladder smooth muscle cells and 8.2 +/- 0.051 in submandibular gland cells (n = 5). The pKi value of solifenacin was almost equivalent to the values of oxybutynin, tolterodine and darifenacin in bladder smooth muscle cells (8.7, 8.5 and 8.4, respectively), while being lower than those in submandibular gland cells (9.0, 8.7 and 8.8, respectively). The bladder-selectivity index (Ki ratio: submandibular gland/bladder) for solifenacin (2.1) was statistically higher, moreover, than those for oxybutynin, tolterodine and darifenacin (0.51, 0.65 and 0.46, respectively). These findings consequently indicate solifenacin's unique profile in terms of its selectivity for bladder smooth muscle cells over salivary gland cells in non-human primates, relative to oxybutynin, tolterodine and darifenacin. Solifenacin may, therefore, confer a promising therapeutic advantage for reducing adverse effects, such as dry mouth, exhibited by current antimuscarinic therapy for overactive bladder.
Kobayashi
Seiji
S
Pharmacology Laboratories Applied Pharmacology Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba-city, Ibaraki 305-8585, Japan. kobayashi.seiji@yamanouchi.co.jp
Ikeda
Ken
K
Miyata
Keiji
K
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010665:Phenylpropanolamine; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology*; D000069464:Solifenacin Succinate; D013363:Submandibular Gland / Q000187:drug effects* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011812:Quinuclidines; D044005:Tetrahydroisoquinolines; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D002217:Carbachol; C101207:darifenacin; C005419:oxybutynin; D000069464:Solifenacin Succinate; D002118:Calcium