Pharmacokinetics and toxicokinetics of d-serine in rats

Abstract

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 multiexponentially 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 μmol/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.

Keywords: GC–MS; Nephrotoxicity; Pharmacokinetics; Toxicokinetics; d-serine.