Journal
DRUG METABOLISM AND DISPOSITION
Volume 40, Issue 11, Pages 2067-2073Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.112.046482
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Funding
- National Institutes of Health National Institute of Mental Health [R01-MH091387]
- Johns Hopkins Brain Science Institute NeuroTranslational Drug Discovery program
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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 wildtype mice (t1/2 = 1.2 h), sustained drug levels over the course of 4 h (t1/2 > 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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