RT Journal Article
SR Electronic
T1 Pharmacokinetics of Oral <span class="sc">d</span>-Serine in <span class="sc">d</span>-Amino Acid Oxidase Knockout Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2067
OP 2073
DO 10.1124/dmd.112.046482
VO 40
IS 11
A1 Rais, Rana
A1 Thomas, Ajit G.
A1 Wozniak, Krystyna
A1 Wu, Ying
A1 Jaaro-Peled, Hanna
A1 Sawa, Akira
A1 Strick, Christine A.
A1 Engle, Sandra J.
A1 Brandon, Nicholas J.
A1 Rojas, Camilo
A1 Slusher, Barbara S.
A1 Tsukamoto, Takashi
YR 2012
UL http://dmd.aspetjournals.org/content/40/11/2067.abstract
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.