title: Comparative evaluation of exocrine muscarinic receptor binding characteristics and inhibition of salivation of solifenacin in mice.
abstract: Anticholinergic agents such as oxybutynin are clinically useful in the treatment of overactive bladder. However, oral administration of oxybutynin is frequently accompanied by side effects such as dry mouth, and novel bladder-selective anticholinergic agents such as solifenacin and tolterodine are now under development. The aim of the present study was to characterize the suppression of cholinergic salivation and exocrine muscarinic receptor binding of solifenacin on oral administration to mice in comparison with those of oxybutynin. Results showed that both drugs produced a significant increase in K(d) values for specific [N-Methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the mouse submaxillary gland, compared with control values. However, this enhancement in K(d) values was significantly smaller with solifenacin than with oxybutynin. Moreover, the inhibitory effect of solifenacin on pilocarpine-induced salivary secretion was significantly weaker than that of oxybutynin. Solifenacin dissociated more readily from muscarinic receptors in the mouse submaxillary gland than oxybutynin. In conclusion, the present study indicates that the weak suppression of cholinergic salivation by solifenacin compared with oxybutynin may be partially attributed to its relatively fast dissociation kinetics from exocrine muscarinic receptors.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Oki
authors.forename: Chihiro
authors.initials: C
authors.lastname: Takeuchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D007700:Kinetics; D008297:Male; D008333:Mandelic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010276:Parasympatholytics / Q000494:pharmacology; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D012463:Saliva / Q000187:drug effects / Q000378:metabolism; D012472:Salivation / Q000187:drug effects / Q000502:physiology*; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D008333:Mandelic Acids; D010276:Parasympatholytics; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; C005419:oxybutynin; D000069464:Solifenacin Succinate