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.