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Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein
Although blonanserin, a novel atypical antipsychotic agent with dopamine D2/serotonin 5-HT2A antagonistic properties, displays good brain distribution, the mechanism of this distribution has not been clarified. P-glycoprotein [(P-gp) or multidrug resistance protein 1 (MDR1)] is an efflux transporter...
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Published in: | Progress in neuro-psychopharmacology & biological psychiatry 2012-10, Vol.39 (1), p.156-162 |
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creator | Inoue, Tomoko Osada, Kenichi Tagawa, Masaaki Ogawa, Yuriko Haga, Toshiaki Sogame, Yoshihisa Hashizume, Takanori Watanabe, Takashi Taguchi, Atsushi Katsumata, Takashi Yabuki, Masashi Yamaguchi, Noboru |
description | Although blonanserin, a novel atypical antipsychotic agent with dopamine D2/serotonin 5-HT2A antagonistic properties, displays good brain distribution, the mechanism of this distribution has not been clarified. P-glycoprotein [(P-gp) or multidrug resistance protein 1 (MDR1)] is an efflux transporter expressed in the brain and plays an important role in limiting drug entry into the central nervous system (CNS). In particular, P-gp can affect the pharmacokinetics and efficacy of antipsychotics, and exacerbate or soothe their adverse effects. In this study, we conducted in vitro and in vivo experiments to determine whether blonanserin is a P-gp substrate. Risperidone and its active metabolite 9-hydroxyrisperidone, both of which are P-gp substrates, were used as reference drugs. Affinity of blonanserin, risperidone, and 9-hydroxyrisperidone for P-gp was evaluated by in vitro transcellular transport across LLC-PK1, human MDR1 cDNA-transfected LLC-PK1 (LLC-MDR1), and mouse Mdr1a cDNA-transfected LLC-PK1 (LLC-Mdr1a). In addition, pharmacokinetic parameters in the brain and plasma (B/P ratio) of test compounds were measured in mdr1a/1b knockout (KO) and wild-type (WT) mice. The results of in vitro experiments revealed that P-gp does not actively transport blonanserin as a substrate in humans or mice. In addition, blonanserin displayed comparable B/P ratios in KO and WT mice, whereas B/P ratios of risperidone and 9-hydroxyrisperidone differed markedly in these animals. Our results indicate that blonanserin is not a P-gp substrate and therefore its brain distribution is unlikely to be affected by this transporter.
► Blonanserin is not a P-gp substrate in both in vitro and in vivo experiments. ► Brain distribution of blonanserin is unlikely to be affected by P-gp. ► For non P-gp substrate blonanserin, there is no need to worry about P-gp-mediated DDI. |
doi_str_mv | 10.1016/j.pnpbp.2012.06.005 |
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► Blonanserin is not a P-gp substrate in both in vitro and in vivo experiments. ► Brain distribution of blonanserin is unlikely to be affected by P-gp. ► For non P-gp substrate blonanserin, there is no need to worry about P-gp-mediated DDI.</description><identifier>ISSN: 0278-5846</identifier><identifier>EISSN: 1878-4216</identifier><identifier>DOI: 10.1016/j.pnpbp.2012.06.005</identifier><identifier>PMID: 22691713</identifier><identifier>CODEN: PNPPD7</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Animals ; Antipsychotic Agents - blood ; Antipsychotic Agents - pharmacokinetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Biological and medical sciences ; Biological Transport, Active ; Blonanserin ; Brain ; Brain - metabolism ; Cell Line, Transformed ; Central nervous system ; Dopamine D2 receptors ; Drugs ; Humans ; Isoxazoles - blood ; Isoxazoles - pharmacokinetics ; Knockout mice ; LLC-PK1 Cells ; Medical sciences ; Metabolites ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; Multidrug resistance ; Neuroleptics ; Neuropharmacology ; P-Glycoprotein ; P-gp ; P-gp-mediated DDI ; Paliperidone Palmitate ; Pharmacokinetics ; Pharmacology. Drug treatments ; Piperazines - blood ; Piperazines - pharmacokinetics ; Piperidines - blood ; Piperidines - pharmacokinetics ; Psycholeptics: tranquillizer, neuroleptic ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Pyrimidines - blood ; Pyrimidines - pharmacokinetics ; Risperidone ; Risperidone - blood ; Risperidone - pharmacokinetics ; Serotonin S2 receptors ; Side effects ; Swine</subject><ispartof>Progress in neuro-psychopharmacology & biological psychiatry, 2012-10, Vol.39 (1), p.156-162</ispartof><rights>2012 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-9e3d557218b5bcf347ac5a58b34d0d780752c7589341156040c34240febb9cec3</citedby><cites>FETCH-LOGICAL-c422t-9e3d557218b5bcf347ac5a58b34d0d780752c7589341156040c34240febb9cec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26294138$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22691713$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Inoue, Tomoko</creatorcontrib><creatorcontrib>Osada, Kenichi</creatorcontrib><creatorcontrib>Tagawa, Masaaki</creatorcontrib><creatorcontrib>Ogawa, Yuriko</creatorcontrib><creatorcontrib>Haga, Toshiaki</creatorcontrib><creatorcontrib>Sogame, Yoshihisa</creatorcontrib><creatorcontrib>Hashizume, Takanori</creatorcontrib><creatorcontrib>Watanabe, Takashi</creatorcontrib><creatorcontrib>Taguchi, Atsushi</creatorcontrib><creatorcontrib>Katsumata, Takashi</creatorcontrib><creatorcontrib>Yabuki, Masashi</creatorcontrib><creatorcontrib>Yamaguchi, Noboru</creatorcontrib><title>Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein</title><title>Progress in neuro-psychopharmacology & biological psychiatry</title><addtitle>Prog Neuropsychopharmacol Biol Psychiatry</addtitle><description>Although blonanserin, a novel atypical antipsychotic agent with dopamine D2/serotonin 5-HT2A antagonistic properties, displays good brain distribution, the mechanism of this distribution has not been clarified. P-glycoprotein [(P-gp) or multidrug resistance protein 1 (MDR1)] is an efflux transporter expressed in the brain and plays an important role in limiting drug entry into the central nervous system (CNS). In particular, P-gp can affect the pharmacokinetics and efficacy of antipsychotics, and exacerbate or soothe their adverse effects. In this study, we conducted in vitro and in vivo experiments to determine whether blonanserin is a P-gp substrate. Risperidone and its active metabolite 9-hydroxyrisperidone, both of which are P-gp substrates, were used as reference drugs. Affinity of blonanserin, risperidone, and 9-hydroxyrisperidone for P-gp was evaluated by in vitro transcellular transport across LLC-PK1, human MDR1 cDNA-transfected LLC-PK1 (LLC-MDR1), and mouse Mdr1a cDNA-transfected LLC-PK1 (LLC-Mdr1a). In addition, pharmacokinetic parameters in the brain and plasma (B/P ratio) of test compounds were measured in mdr1a/1b knockout (KO) and wild-type (WT) mice. The results of in vitro experiments revealed that P-gp does not actively transport blonanserin as a substrate in humans or mice. In addition, blonanserin displayed comparable B/P ratios in KO and WT mice, whereas B/P ratios of risperidone and 9-hydroxyrisperidone differed markedly in these animals. Our results indicate that blonanserin is not a P-gp substrate and therefore its brain distribution is unlikely to be affected by this transporter.
► Blonanserin is not a P-gp substrate in both in vitro and in vivo experiments. ► Brain distribution of blonanserin is unlikely to be affected by P-gp. ► For non P-gp substrate blonanserin, there is no need to worry about P-gp-mediated DDI.</description><subject>Animals</subject><subject>Antipsychotic Agents - blood</subject><subject>Antipsychotic Agents - pharmacokinetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biological Transport, Active</subject><subject>Blonanserin</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Cell Line, Transformed</subject><subject>Central nervous system</subject><subject>Dopamine D2 receptors</subject><subject>Drugs</subject><subject>Humans</subject><subject>Isoxazoles - blood</subject><subject>Isoxazoles - pharmacokinetics</subject><subject>Knockout mice</subject><subject>LLC-PK1 Cells</subject><subject>Medical sciences</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Mice, Knockout</subject><subject>Multidrug resistance</subject><subject>Neuroleptics</subject><subject>Neuropharmacology</subject><subject>P-Glycoprotein</subject><subject>P-gp</subject><subject>P-gp-mediated DDI</subject><subject>Paliperidone Palmitate</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - blood</subject><subject>Piperazines - pharmacokinetics</subject><subject>Piperidines - blood</subject><subject>Piperidines - pharmacokinetics</subject><subject>Psycholeptics: tranquillizer, neuroleptic</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Pyrimidines - blood</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Risperidone</subject><subject>Risperidone - blood</subject><subject>Risperidone - pharmacokinetics</subject><subject>Serotonin S2 receptors</subject><subject>Side effects</subject><subject>Swine</subject><issn>0278-5846</issn><issn>1878-4216</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNqNkUuLFDEUhYMoTjv6CwTJRnBhlXlXauFCB18woAtdhyR1a0xTnZRJeqD-vRm71Z24yiV8557LOQg9paSnhKpX-36Nq1t7RijrieoJkffQjupBd4JRdR_tCGuz1EJdoEel7AkhlBP-EF0wpkY6UL5D4e2Soo0FcogvscUx3cKCbd3W4G0bYg1r2fz3VIPH9gZibUjF1tfQwA3X3MRryhUmbAsuR1faVwXsNvylu1k2n9acKoT4GD2Y7VLgyfm9RN_ev_t69bG7_vzh09Wb684Lxmo3Ap-kHBjVTjo_czFYL63UjouJTIMmg2R-kHrkglKpiCCeCybIDM6NHjy_RC9Oe5vvjyOUag6heFgWGyEdi6GEazmKYVT_gzaPkTPaUH5CfU6lZJjNmsPB5q1B5q4Osze_6jB3dRiiTKujqZ6dDY7uANMfze_8G_D8DNjS8p5bmj6Uv5xio6BcN-71iYOW3G2AbIoPED1MIYOvZkrhn4f8BNuJqh4</recordid><startdate>20121001</startdate><enddate>20121001</enddate><creator>Inoue, Tomoko</creator><creator>Osada, Kenichi</creator><creator>Tagawa, Masaaki</creator><creator>Ogawa, Yuriko</creator><creator>Haga, Toshiaki</creator><creator>Sogame, Yoshihisa</creator><creator>Hashizume, Takanori</creator><creator>Watanabe, Takashi</creator><creator>Taguchi, Atsushi</creator><creator>Katsumata, Takashi</creator><creator>Yabuki, Masashi</creator><creator>Yamaguchi, Noboru</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><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>7X8</scope><scope>7TK</scope></search><sort><creationdate>20121001</creationdate><title>Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein</title><author>Inoue, Tomoko ; Osada, Kenichi ; Tagawa, Masaaki ; Ogawa, Yuriko ; Haga, Toshiaki ; Sogame, Yoshihisa ; Hashizume, Takanori ; Watanabe, Takashi ; Taguchi, Atsushi ; Katsumata, Takashi ; Yabuki, Masashi ; Yamaguchi, Noboru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-9e3d557218b5bcf347ac5a58b34d0d780752c7589341156040c34240febb9cec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antipsychotic Agents - blood</topic><topic>Antipsychotic Agents - pharmacokinetics</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biological Transport, Active</topic><topic>Blonanserin</topic><topic>Brain</topic><topic>Brain - metabolism</topic><topic>Cell Line, Transformed</topic><topic>Central nervous system</topic><topic>Dopamine D2 receptors</topic><topic>Drugs</topic><topic>Humans</topic><topic>Isoxazoles - blood</topic><topic>Isoxazoles - pharmacokinetics</topic><topic>Knockout mice</topic><topic>LLC-PK1 Cells</topic><topic>Medical sciences</topic><topic>Metabolites</topic><topic>Mice</topic><topic>Mice, Inbred Strains</topic><topic>Mice, Knockout</topic><topic>Multidrug resistance</topic><topic>Neuroleptics</topic><topic>Neuropharmacology</topic><topic>P-Glycoprotein</topic><topic>P-gp</topic><topic>P-gp-mediated DDI</topic><topic>Paliperidone Palmitate</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - blood</topic><topic>Piperazines - pharmacokinetics</topic><topic>Piperidines - blood</topic><topic>Piperidines - pharmacokinetics</topic><topic>Psycholeptics: tranquillizer, neuroleptic</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Pyrimidines - blood</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Risperidone</topic><topic>Risperidone - blood</topic><topic>Risperidone - pharmacokinetics</topic><topic>Serotonin S2 receptors</topic><topic>Side effects</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Inoue, Tomoko</creatorcontrib><creatorcontrib>Osada, Kenichi</creatorcontrib><creatorcontrib>Tagawa, Masaaki</creatorcontrib><creatorcontrib>Ogawa, Yuriko</creatorcontrib><creatorcontrib>Haga, Toshiaki</creatorcontrib><creatorcontrib>Sogame, Yoshihisa</creatorcontrib><creatorcontrib>Hashizume, Takanori</creatorcontrib><creatorcontrib>Watanabe, Takashi</creatorcontrib><creatorcontrib>Taguchi, Atsushi</creatorcontrib><creatorcontrib>Katsumata, Takashi</creatorcontrib><creatorcontrib>Yabuki, Masashi</creatorcontrib><creatorcontrib>Yamaguchi, Noboru</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Progress in neuro-psychopharmacology & biological psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Inoue, Tomoko</au><au>Osada, Kenichi</au><au>Tagawa, Masaaki</au><au>Ogawa, Yuriko</au><au>Haga, Toshiaki</au><au>Sogame, Yoshihisa</au><au>Hashizume, Takanori</au><au>Watanabe, Takashi</au><au>Taguchi, Atsushi</au><au>Katsumata, Takashi</au><au>Yabuki, Masashi</au><au>Yamaguchi, Noboru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein</atitle><jtitle>Progress in neuro-psychopharmacology & biological psychiatry</jtitle><addtitle>Prog Neuropsychopharmacol Biol Psychiatry</addtitle><date>2012-10-01</date><risdate>2012</risdate><volume>39</volume><issue>1</issue><spage>156</spage><epage>162</epage><pages>156-162</pages><issn>0278-5846</issn><eissn>1878-4216</eissn><coden>PNPPD7</coden><abstract>Although blonanserin, a novel atypical antipsychotic agent with dopamine D2/serotonin 5-HT2A antagonistic properties, displays good brain distribution, the mechanism of this distribution has not been clarified. P-glycoprotein [(P-gp) or multidrug resistance protein 1 (MDR1)] is an efflux transporter expressed in the brain and plays an important role in limiting drug entry into the central nervous system (CNS). In particular, P-gp can affect the pharmacokinetics and efficacy of antipsychotics, and exacerbate or soothe their adverse effects. In this study, we conducted in vitro and in vivo experiments to determine whether blonanserin is a P-gp substrate. Risperidone and its active metabolite 9-hydroxyrisperidone, both of which are P-gp substrates, were used as reference drugs. Affinity of blonanserin, risperidone, and 9-hydroxyrisperidone for P-gp was evaluated by in vitro transcellular transport across LLC-PK1, human MDR1 cDNA-transfected LLC-PK1 (LLC-MDR1), and mouse Mdr1a cDNA-transfected LLC-PK1 (LLC-Mdr1a). In addition, pharmacokinetic parameters in the brain and plasma (B/P ratio) of test compounds were measured in mdr1a/1b knockout (KO) and wild-type (WT) mice. The results of in vitro experiments revealed that P-gp does not actively transport blonanserin as a substrate in humans or mice. In addition, blonanserin displayed comparable B/P ratios in KO and WT mice, whereas B/P ratios of risperidone and 9-hydroxyrisperidone differed markedly in these animals. Our results indicate that blonanserin is not a P-gp substrate and therefore its brain distribution is unlikely to be affected by this transporter.
► Blonanserin is not a P-gp substrate in both in vitro and in vivo experiments. ► Brain distribution of blonanserin is unlikely to be affected by P-gp. ► For non P-gp substrate blonanserin, there is no need to worry about P-gp-mediated DDI.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>22691713</pmid><doi>10.1016/j.pnpbp.2012.06.005</doi><tpages>7</tpages></addata></record> |
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subjects | Animals Antipsychotic Agents - blood Antipsychotic Agents - pharmacokinetics ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Biological and medical sciences Biological Transport, Active Blonanserin Brain Brain - metabolism Cell Line, Transformed Central nervous system Dopamine D2 receptors Drugs Humans Isoxazoles - blood Isoxazoles - pharmacokinetics Knockout mice LLC-PK1 Cells Medical sciences Metabolites Mice Mice, Inbred Strains Mice, Knockout Multidrug resistance Neuroleptics Neuropharmacology P-Glycoprotein P-gp P-gp-mediated DDI Paliperidone Palmitate Pharmacokinetics Pharmacology. Drug treatments Piperazines - blood Piperazines - pharmacokinetics Piperidines - blood Piperidines - pharmacokinetics Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Pyrimidines - blood Pyrimidines - pharmacokinetics Risperidone Risperidone - blood Risperidone - pharmacokinetics Serotonin S2 receptors Side effects Swine |
title | Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein |
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