TY - JOUR
T1 - Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice
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
PY - 2012/11
Y1 - 2012/11
N2 - 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 (t1/2 = 1.2 h), sustained drug levels over the course of 4 h (t 1/2 > 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.
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 (t1/2 = 1.2 h), sustained drug levels over the course of 4 h (t 1/2 > 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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U2 - 10.1124/dmd.112.046482
DO - 10.1124/dmd.112.046482
M3 - Article
C2 - 22837388
AN - SCOPUS:84867373455
SN - 0090-9556
VL - 40
SP - 2067
EP - 2073
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 11
ER -