In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats.
Solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the in vitro and in vivo bladder selectivity profile of solifenacin over salivary gland in the same animal species, and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin and atropine. Solifenacin and the other antimuscarinic drugs inhibited carbachol-induced increases in intracellular Ca(2+) levels in bladder smooth muscle cells and salivary gland cells isolated from rats in a concentration-dependent manner. The inhibitory effect of solifenacin for bladder smooth muscle cells (pK(i)=8.12) was 3.6-fold more potent than that for salivary gland cells (pK(i)=7.57). In contrast, the inhibitory effects of the other antimuscarinic drugs for bladder smooth muscle cells were 1.7- to 2.2-fold more potent than those for salivary gland cells. In anesthetized rats, solifenacin dose-dependently inhibited carbachol-induced intravesical pressure elevation and salivary secretion, and exhibited functional selectivity (3.7- to 6.5-fold) for urinary bladder over salivary gland. Tolterodine was also 2.2- to 2.4-fold more selective in inhibition of bladder response. In contrast, oxybutynin, darifenacin and atropine did not show functional selectivity for urinary bladder. These results indicate that solifenacin exerts greater selectivity for urinary bladder over salivary gland than tolterodine, oxybutynin, darifenacin and atropine, and may consequently provide symptomatic benefit in the treatment of overactive bladder with less dry mouth than currently used antimuscarinic drugs.
Ohtake
Akiyoshi
A
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. ohtake@yamanouchi.co.jp
Ukai
Masashi
M
Hatanaka
Toshiki
T
Kobayashi
Seiji
S
Ikeda
Ken
K
Sato
Shuichi
S
Miyata
Keiji
K
Sasamata
Masao
M
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003408:Cresols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008333:Mandelic Acids / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D010665:Phenylpropanolamine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000069464:Solifenacin Succinate; D013363:Submandibular Gland / Q000187:drug effects* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / 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; D001285:Atropine; C101207:darifenacin; C005419:oxybutynin; D000069464:Solifenacin Succinate; D002118:Calcium