Muscarinic receptor binding, plasma concentration and inhibition of salivation after oral administration of a novel antimuscarinic agent, solifenacin succinate in mice.
1 A novel muscarinic receptor antagonist, solifenacin succinate, inhibited specific binding of [N-methyl-(3)H]-scopolamine ([(3)H]-NMS) in the mouse bladder, submaxillary gland and heart in a concentration-dependent manner. This inhibitory effect was greatest in the submaxillary gland, followed by the bladder and heart. 2 After oral administration of oxybutynin (76.1 micromol kg(-1)) or solifenacin (62.4, 208 micromol kg(-1)), a significant dose- and time-dependent increase in K(D) values for specific [(3)H]-NMS binding was seen in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values. The increase in K(D) induced by oxybutynin in each tissue reached a maximum 0.5 h after oral administration and then rapidly declined, while that induced by solifenacin was greatest 2 h after administration and was maintained for at least 6 or 12 h, depending on the dose. The muscarinic receptor binding of oral solifenacin was slower in onset and of a longer duration than that of oxybutynin. 3 Plasma concentrations of oxybutynin and its active metabolite (N-desethyl-oxybutynin, DEOB) were maximum 0.5 h after its oral administration and then declined rapidly. Oral solifenacin persisted in the blood for longer than oxybutynin. 4 Pilocarpine-induced salivary secretion in mice was significantly reduced by oral administration of solifenacin and was completely abolished 0.5 h after oral oxybutynin. Although the suppression induced by solifenacin was more persistent than that due to oxybutynin, the antagonistic effect of solifenacin on the dose-response curves to pilocarpine was significantly weaker than that of oxybutynin. It is concluded that oral solifenacin persistently binds to muscarinic receptors in tissues expressing the M(3) subtype, such as the bladder.
Oki
Tomomi
T
Department of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Sato
Shuichi
S
Miyata
Keiji
K
Yamada
Shizuo
S
D000284:Administration, Oral; D000818:Animals; D003864:Depression, Chemical; D066298:In Vitro Techniques; D008297:Male; D008333:Mandelic Acids / Q000097:blood / Q000494:pharmacology; D051379:Mice; D018727:Muscarinic Antagonists / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D011812:Quinuclidines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012469:Salivary Glands / Q000378:metabolism; D012472:Salivation / Q000187:drug effects*; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001743:Urinary Bladder / Q000378:metabolism
D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; C032681:desethyloxybutynin; C005419:oxybutynin; D000069464:Solifenacin Succinate