Pharmacokinetics and toxicokinetics of D-serine in rats

In the mammalian brain, D-serine acts as a co-agonist at the glycine-binding site on the N-methyl-D-aspartate receptor. Because plasma D-serine levels are significantly lower in patients with schizophrenia than in healthy subjects, D-serine has been proposed as a potential therapeutic agent for schizophrenia treatment. However, D-serine has a nephrotoxic effect in rats at high doses. The purpose of this study was to investigate the relationship between the plasma kinetics of D-serine and nephrotoxicity in rats. We administered D-serine intravenously (iv), orally (po), or intraperitoneally (ip) to male Wistar rats, and performed gas chromatography-mass spectrometry to measure the plasma concentrations of D- and L-serine. After iv administration (0.1 mmol/kg body weight (bw)), plasma D-serine declined multi-exponentially with an elimination t(1/2) of 108 +/- 16 min, and the total clearance was 7.9 +/- 0.9 ml/min/kg bw. The oral bioavailability of D-serine was estimated to be 94 +/- 27%. To evaluate the dose-response relationship of D-serine-induced kidney injury and the plasma kinetics of D-serine, we injected D-serine into rats ip in doses ranging from 0.6 to 4.8 mmol/kg bw. Twenty-four hours after D-serine administration, histological changes indicating renal damage were observed in the kidneys of rats who received D-serine at doses of 1.8-4.8 mmol/kg bw; the severity of the tubular injury increased with increasing D-serine dose. When the C-max value of D-serine was approximately >2 mu mol/ml, the plasma creatinine increased remarkably 24 h after D-serine administration. This suggests that the C-max of D-serine could be a good predictor of D-serine-induced nephrotoxicity. (C) 2018 Elsevier B.V. All rights reserved.