Blonanserin, a novel atypical antipsychotic agent not actively transported as substrate by P-glycoprotein

• 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
• Format: Article
• Language: English
• 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
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2012.06.005

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.