title: Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.
abstract: It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second-generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D-KYN as the substrate. DAO inhibitors 3-methylpyrazole-5-carboxylic acid and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose-dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 ± 0.47 μM and 4.70 ± 0.17 μM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy.
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University.
authors.forename: Miho
authors.initials: M
authors.lastname: Shishikura
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hakariya
authors.forename: Sumiko
authors.initials: S
authors.lastname: Iwasa
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshio
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ichiba
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yorita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukui
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukushima
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D003605:D-Amino-Acid Oxidase / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018967:Risperidone / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D010880:Piperidines; C079310:blonanserin; D003605:D-Amino-Acid Oxidase; D018967:Risperidone