PT - JOURNAL ARTICLE AU - Rais, Rana AU - Thomas, Ajit G. AU - Wozniak, Krystyna AU - Wu, Ying AU - Jaaro-Peled, Hanna AU - Sawa, Akira AU - Strick, Christine A. AU - Engle, Sandra J. AU - Brandon, Nicholas J. AU - Rojas, Camilo AU - Slusher, Barbara S. AU - Tsukamoto, Takashi TI - Pharmacokinetics of Oral <span class="sc">d</span>-Serine in <span class="sc">d</span>-Amino Acid Oxidase Knockout Mice AID - 10.1124/dmd.112.046482 DP - 2012 Nov 01 TA - Drug Metabolism and Disposition PG - 2067--2073 VI - 40 IP - 11 4099 - http://dmd.aspetjournals.org/content/40/11/2067.short 4100 - http://dmd.aspetjournals.org/content/40/11/2067.full SO - Drug Metab Dispos2012 Nov 01; 40 AB - 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 (t½ = 1.2 h), sustained drug levels over the course of 4 h (t½ &gt; 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.