| In vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy by antimuscarinic agents for overactive bladder treatment. | |
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MedLine Citation:
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PMID: 18326811 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Shuji Maruyama; Hideo Tsukada; Shingo Nishiyama; Takeharu Kakiuchi; Dai Fukumoto; Naoto Oku; Shizuo Yamada |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-03-07 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 325 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-05-16 Completed Date: 2008-06-16 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 774-81 Citation Subset: IM |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Autoradiography Brain / metabolism*, radionuclide imaging Carbon Radioisotopes / diagnostic use Male Muscarinic Antagonists / pharmacokinetics* Rats Rats, Sprague-Dawley Receptors, Muscarinic / metabolism* Urinary Bladder, Overactive / drug therapy, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Carbon Radioisotopes; 0/Muscarinic Antagonists; 0/Receptors, Muscarinic |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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