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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
Main Authors: Inoue, Tomoko, Osada, Kenichi, Tagawa, Masaaki, Ogawa, Yuriko, Haga, Toshiaki, Sogame, Yoshihisa, Hashizume, Takanori, Watanabe, Takashi, Taguchi, Atsushi, Katsumata, Takashi, Yabuki, Masashi, Yamaguchi, Noboru
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cites cdi_FETCH-LOGICAL-c422t-9e3d557218b5bcf347ac5a58b34d0d780752c7589341156040c34240febb9cec3
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container_title Progress in neuro-psychopharmacology & biological psychiatry
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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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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. 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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 &amp; 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&amp;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 &amp; 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. 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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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identifier ISSN: 0278-5846
ispartof Progress in neuro-psychopharmacology & biological psychiatry, 2012-10, Vol.39 (1), p.156-162
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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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