title: D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog.
abstract: D-serine has been shown to improve positive, negative, and cognitive symptoms when used as add-on therapy for the treatment of schizophrenia. However, D-serine has to be administered at high doses to observe clinical effects. This is thought to be due to D-serine undergoing oxidation by D-amino-acid oxidase (DAAO) before it reaches the brain. Consequently, co-administration of D-serine with a DAAO inhibitor could be a way to lower the D-serine dose required to treat schizophrenia. Early studies in rodents to evaluate this hypothesis showed that concomitant administration of structurally distinct DAAO inhibitors with D-serine enhanced plasma and brain D-serine levels in rodents compared with administration of D-serine alone. In the present work we used three potent DAAO inhibitors and confirmed previous results in mice. In a follow-up effort, we evaluated plasma D-serine levels in monkeys after oral administration of D-serine in the presence or absence of these DAAO inhibitors. Even though the compounds reached steady state plasma concentrations exceeding their Ki values by >60-fold, plasma D-serine levels remained the same as those in the absence of DAAO inhibitors. Similar results were obtained with dogs. In summary, in contrast to rodents, DAAO inhibition in monkeys and dogs did not influence the exposure to exogenously administered D-serine. Results could be due to differences in D-serine metabolism and/or clearance mechanisms and suggest that the role of DAAO in the metabolism of D-serine is different across species. These data provide caution regarding the utility of DAAO inhibition for patients with schizophrenia.
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.|Department of Molecular and Comparative Pathobiology, Baltimore, MD, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Alt
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Baltimore, MD, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Ator
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.
authors.forename: Niyada
authors.initials: N
authors.lastname: Hin
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Wozniak
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.|Department of Neurology, Baltimore, MD, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.|Department of Neurology, Baltimore, MD, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Johns Hopkins Drug Discovery, Baltimore, MD, USA.|Department of Psychiatry and Behavioral Sciences, Baltimore, MD, USA.|Department of Neurology, Baltimore, MD, USA.|Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D048529:Papio hamadryas; D012694:Serine / Q000097:blood*; D013045:Species Specificity
chemical_list: C531067:5-chlorobenzo(d)isoxazol-3-ol; D007555:Isoxazoles; D012694:Serine; D003605:D-Amino-Acid Oxidase