A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder
Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here...
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| creator | Nakatani, Yosuke Suzuki, Michiyuki Tokunaga, Masaki Maeda, Jun Sakai, Miyuki Ishihara, Hiroki Yoshinaga, Takashi Takenaka, Osamu Zhang, Ming-Rong Suhara, Tetsuya Higuchi, Makoto |
| description | Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB. |
| doi_str_mv | 10.1371/journal.pone.0075040 |
| format | Article |
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Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0075040</identifier><identifier>PMID: 24086433</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>8-Hydroxy-2-(di-n-propylamino)tetralin - administration & dosage ; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology ; Administration, Oral ; Animal models ; Animals ; Biomarkers ; Bladder ; Brain ; Brain research ; Chemical compounds ; Computer Simulation ; Cytochrome ; Dopamine ; Drug dosages ; Emission analysis ; Ethics ; Health aspects ; Hippocampus - drug effects ; Hippocampus - metabolism ; In vivo methods and tests ; Laboratory animals ; Ligands ; Mathematical models ; Medical imaging ; Medicine ; Microsomes - drug effects ; Microsomes - metabolism ; Occupancy ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Phenols (Class of compounds) ; Piperidines - chemistry ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Piperidines - therapeutic use ; Plasma ; Positron emission ; Positron emission tomography ; Protein Binding - drug effects ; Psychotropic drugs ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT1A - metabolism ; Receptors ; Reflex - drug effects ; Rodents ; Serotonin ; Serotonin S1 receptors ; Studies ; Superior Colliculi - drug effects ; Time Factors ; Tomography ; Urinary bladder ; Urinary Bladder, Overactive - diagnostic imaging ; Urinary Bladder, Overactive - drug therapy ; Urinary Bladder, Overactive - physiopathology ; Urinary incontinence ; Urination ; Urination - drug effects</subject><ispartof>PloS one, 2013-09, Vol.8 (9), p.e75040</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Nakatani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. 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diagnostic imaging</subject><subject>Urinary Bladder, Overactive - drug therapy</subject><subject>Urinary Bladder, Overactive - physiopathology</subject><subject>Urinary incontinence</subject><subject>Urination</subject><subject>Urination - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9GK1DAUhoso7rr6BqIBQfBiZpOmaTs3wrCsOrCwoqu3IU1PZjJ2mm6SDs6z-LKecTrLFBSkF2lOvvPn5E9OkrxkdMp4wS7Xrvetaqada2FKaSFoRh8l52zG00meUv745P8seRbCmlLByzx_mpylGS3zjPPz5NechI1qmolqLY6kWym_Udr9sC1Eqy-P83rXqo3V5PP1HQmxr3fEGaKhjR6TAngXXWtbwubEg4YuOk-c1n2nWr0j1Y4o0rmIuEU8rsCrDnrUJ2qJQWL2-BajOtotkKpRdQ3-efLEqCbAi2G8SL59uL67-jS5uf24uJrfTHRJ0zgxtCxyalIK2tSM5gwYo6xMRUZznYuCc1qWs2rGhGFVXu3PbqBODQehNTMZv0heH3S7xgU5-Boky7gQM_QpRWJxIGqn1rLzaJXfSaes_BNwfimVx-M0IDUTpRKlwI14VtSVEjXoSmUVcFbkKket98NufbWBevBwJDpeae1KLt1W8qJklO_LfTMIeHffQ4j_KHmglgqrsq1xKKY3Nmg5z1CJp2geUtO_UPjVgLeNL8tYjI8S3o0SkInwMy5VH4JcfP3y_-zt9zH79oRdgWriKrgG34hrwxjMDqD2LgQP5sE5RuW-MY5uyH1jyKExMO3VqesPScdO4L8BLzwLFQ</recordid><startdate>20130923</startdate><enddate>20130923</enddate><creator>Nakatani, Yosuke</creator><creator>Suzuki, Michiyuki</creator><creator>Tokunaga, Masaki</creator><creator>Maeda, Jun</creator><creator>Sakai, Miyuki</creator><creator>Ishihara, Hiroki</creator><creator>Yoshinaga, Takashi</creator><creator>Takenaka, Osamu</creator><creator>Zhang, Ming-Rong</creator><creator>Suhara, Tetsuya</creator><creator>Higuchi, Makoto</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130923</creationdate><title>A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder</title><author>Nakatani, Yosuke ; Suzuki, Michiyuki ; Tokunaga, Masaki ; Maeda, Jun ; Sakai, Miyuki ; Ishihara, Hiroki ; Yoshinaga, Takashi ; Takenaka, Osamu ; Zhang, Ming-Rong ; Suhara, Tetsuya ; Higuchi, Makoto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c802t-f08760f20ecfd1061e1101825406c657330889b915f1b6b2408fed2f3e5cc1f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>8-Hydroxy-2-(di-n-propylamino)tetralin - 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Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24086433</pmid><doi>10.1371/journal.pone.0075040</doi><tpages>e75040</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-09, Vol.8 (9), p.e75040 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1435598642 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 8-Hydroxy-2-(di-n-propylamino)tetralin - administration & dosage 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology Administration, Oral Animal models Animals Biomarkers Bladder Brain Brain research Chemical compounds Computer Simulation Cytochrome Dopamine Drug dosages Emission analysis Ethics Health aspects Hippocampus - drug effects Hippocampus - metabolism In vivo methods and tests Laboratory animals Ligands Mathematical models Medical imaging Medicine Microsomes - drug effects Microsomes - metabolism Occupancy Pharmacodynamics Pharmacokinetics Pharmacology Phenols (Class of compounds) Piperidines - chemistry Piperidines - pharmacokinetics Piperidines - pharmacology Piperidines - therapeutic use Plasma Positron emission Positron emission tomography Protein Binding - drug effects Psychotropic drugs Rats Rats, Sprague-Dawley Receptor, Serotonin, 5-HT1A - metabolism Receptors Reflex - drug effects Rodents Serotonin Serotonin S1 receptors Studies Superior Colliculi - drug effects Time Factors Tomography Urinary bladder Urinary Bladder, Overactive - diagnostic imaging Urinary Bladder, Overactive - drug therapy Urinary Bladder, Overactive - physiopathology Urinary incontinence Urination Urination - drug effects |
| title | A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T00%3A15%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20small-animal%20pharmacokinetic/pharmacodynamic%20PET%20study%20of%20central%20serotonin%201A%20receptor%20occupancy%20by%20a%20potential%20therapeutic%20agent%20for%20overactive%20bladder&rft.jtitle=PloS%20one&rft.au=Nakatani,%20Yosuke&rft.date=2013-09-23&rft.volume=8&rft.issue=9&rft.spage=e75040&rft.pages=e75040-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0075040&rft_dat=%3Cgale_plos_%3EA478132802%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1435598642&rft_id=info:pmid/24086433&rft_galeid=A478132802&rft_doaj_id=oai_doaj_org_article_c158a5856b2347dba5decba4be3176a6&rfr_iscdi=true |