• Rana Rais, Ajit G Thomas, Krystyna Wozniak, Ying Wu, Hanna Jaaro-Peled, Akira Sawa, Christine A Strick, Sandra J Engle, Nicholas J Brandon, Camilo Rojas, Barbara S Slusher, and Takashi Tsukamoto.
• Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
• Drug Metab. Dispos. 2012 Nov 1; 40 (11): 2067-73.

AbstractD-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.

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