title: How does the benzamide antipsychotic amisulpride get into the brain?--An in vitro approach comparing amisulpride with clozapine.
abstract: This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC- and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 muM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, P<1 x 10(-7) cm/s) in the resorptive direction, whereas transport in the secretory direction was observed with a P (+/-SD) of 5.2+/-3.6 x 10(-6) cm/s. The resorptive P of CLZ and DCLZ were 2.3+/-1.2 x 10(-4) and 9.6+/-5.0 x 10(-5) cm/s, respectively. For the permeation across PCEC in the resorptive direction, a P of 1.7+/-2.5 x 10(-6) cm/s was found for AMS and a P of 1.6+/-0.9 x 10(-4) and 2.3+/-1.3 x 10(-5) cm/s was calculated for CLZ and DCLZ, respectively. Both, CLZ and DCLZ, could easily pass both barriers with about a five-fold higher permeation rate of CLZ at the PCEC. The permeation of AMS across the BBB was restricted partly due to an efflux transport. It is thus suggested that AMS reaches its target structures via transport across the blood-CSF barrier.
authors.affiliation: Department of Psychiatry, University of Mainz, Mainz, Germany. sepp@psychiatrie.klinik.uni-mainz.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Härtter
authors.forename: Sabine
authors.initials: S
authors.lastname: Hüwel
authors.forename: Tina
authors.initials: T
authors.lastname: Lohmann
authors.forename: Amal
authors.initials: A
authors.lastname: Abou El Ela
authors.forename: Peter
authors.initials: P
authors.lastname: Langguth
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Galla
mesh_terms: D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001549:Benzamides / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D003024:Clozapine / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D013552:Swine
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; C037689:benzamide; D013469:Sulpiride; D000077582:Amisulpride; D003024:Clozapine