NDLI: In vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy by antimuscarinic agents for overactive bladder treatment.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Maruyama, Shuji Tsukada, Hideo Nishiyama, Shingo Kakiuchi, Takeharu Fukumoto, Dai Oku, Naoto Yamada, Shizuo
Description	Country affiliation: Japan Author Affiliation: Maruyama S ( Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.)
Abstract	We evaluated the effects of five clinically used antimuscarinic agents for overactive bladder (OAB) treatment on in vivo muscarinic receptor binding in rat brain by quantitative autoradiography. There was a dose-related decrease in in vivo specific +N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) binding in each brain region of rats 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. Rank order of the i.v. dose for 50% receptor occupancy (RO(50)) of antimuscarinic agents in rat brain regions was propiverine > solifenacin > tolterodine, oxybutynin. There was a good linear relationship between in vivo (pRO(50) values in the rat hippocampus) and in vitro (pK(i) values in human M(1) receptors) receptor binding activities of propiverine, solifenacin, and tolterodine. The observed RO(50) value of oxybutynin was approximately five times smaller than the predicted in vitro K(i) value. The dose ratios of antimuscarinic agents for the brain receptor occupancy (RO(50)) to the inhibition of carbachol- and volume-induced increases in intravesical pressure (ID(50)), which reflects in vivo selectivity for the urinary bladder over the brain, were greater for solifenacin, tolterodine, and propiverine than oxybutynin. Darifenacin displayed only a slight decrease in specific [11C](+)3-MPB binding in the rat brain regions, and it was not dose-related. In conclusion, in vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy may provide fundamental basis for managing central nervous system (CNS) side effects in antimuscarinic therapy for OAB. It is suggested that in the treatment of OAB, CNS side effects can be avoided by antimuscarinic agents with high selectivity for the urinary bladder over the brain.
File Format	HTM / HTML
ISSN	00223565
Issue Number	3
Volume Number	325
e-ISSN	15210103
Journal	Journal of Pharmacology and Experimental Therapeutics
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Brain Research Support, Non-u.s. Gov't Drug Therapy Rats Rats, Sprague-dawley Male Muscarinic Antagonists Metabolism Discipline Pharmacology Journal Article Autoradiography Receptors, Muscarinic Animals Urinary Bladder, Overactive Discipline Therapeutics Radionuclide Imaging Pharmacokinetics Carbon Radioisotopes
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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