title: Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice.
abstract: D-Amino acid oxidase (DAAO) catalyzes the oxidative deamination of D-amino acids including D-serine, a full agonist at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor. To evaluate the significance of DAAO-mediated metabolism in the pharmacokinetics of oral D-serine, plasma D-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. Although D-serine levels were rapidly diminished in wild-type mice (t(½) = 1.2 h), sustained drug levels over the course of 4 h (t(½) > 10 h) were observed in mice lacking DAAO. Coadministration of D-serine with 6-chlorobenzo[d]isoxazol-3-ol (CBIO), a small-molecule DAAO inhibitor, in wild-type mice resulted in the enhancement of plasma D-serine levels, although CBIO seems to have only temporary effects on the plasma D-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in the clearance of D-serine from the systemic circulation. Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma D-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia.
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Rana
authors: R
authors: Rais
authors: Ajit G
authors: AG
authors: Thomas
authors: Krystyna
authors: K
authors: Wozniak
authors: Ying
authors: Y
authors: Wu
authors: Hanna
authors: H
authors: Jaaro-Peled
authors: Akira
authors: A
authors: Sawa
authors: Christine A
authors: CA
authors: Strick
authors: Sandra J
authors: SJ
authors: Engle
authors: Nicholas J
authors: NJ
authors: Brandon
authors: Camilo
authors: C
authors: Rojas
authors: Barbara S
authors: BS
authors: Slusher
authors: Takashi
authors: T
authors: Tsukamoto
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000378:metabolism; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C531067:5-chlorobenzo(d)isoxazol-3-ol; D007555:Isoxazoles; D012694:Serine; D003605:D-Amino-Acid Oxidase