Abstract
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 NMDA receptor. To evaluate the significance of DAAO-mediated metabolism in pharmacokinetics of oral D-serine, plasma D-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. While D-serine levels were rapidly diminished in wild-type mice (t½ = 1.2 hr), sustained drug levels over the course of 4 h (t½ >10 hr) were observed in mice lacking DAAO. Co-administration 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, though CBIO appears to have only temporary effects to sustain plasma D-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in 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 may have therapeutic implication for the treatment of schizophrenia.
- drug absorption
- drug clearance
- drug design
- enzyme inhibitors
- glucuronidation
- oral absorption
- pharmacokinetics
- phase II drug metabolism
- UDP glucuronyltransferases
- Received May 1, 2012.
- Accepted July 26, 2012.
- The American Society for Pharmacology and Experimental Therapeutics