Pharmacokinetics of Oral d-Serine in d-Amino Acid Oxidase Knockout Mice
| Autor: | Akira Sawa, Barbara S. Slusher, Hanna Jaaro-Peled, Ying Wu, Sandra J. Engle, Camilo Rojas, Christine A. Strick, Nicholas J. Brandon, Takashi Tsukamoto, Krystyna M. Wozniak, Ajit G. Thomas, Rana Rais |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
D-Amino-Acid Oxidase
Male Agonist medicine.drug_class Glucuronidation D-amino acid oxidase Pharmaceutical Science Mice Transgenic Pharmacology Biology Serine Mice medicine Animals Humans Mice Knockout Oxidase test Brain Oxidative deamination Isoxazoles Articles Mice Inbred C57BL Glycine Microsomes Liver Schizophrenia NMDA receptor Female Half-Life |
| Zdroj: | Drug Metabolism and Disposition. 40:2067-2073 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.112.046482 |
| Popis: | 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 (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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|