Pharmacokinetics and toxicokinetics of d-serine in rats

https://doi.org/10.1016/j.jpba.2018.09.026Get rights and content

Highlights

  • We investigated the relationship of d-serine kinetics with nephrotoxicity in rats.

  • Following iv/po/ip d-serine, we measured plasma d-/l-serine with GC–MS.

  • Histology revealed renal damage 24 after ip administration of d-serine at doses of 1.8–4.8 mmol/kg bw.

  • When Cmax of d-serine was >2 μmol/ml, plasma creatinine increased 24 h later.

  • Thus, Cmax of d-serine could be a good predictor of d-serine-induced nephrotoxicity.

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 t1/2 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 Cmax value of d-serine was approximately >2 μmol/ml, the plasma creatinine increased remarkably 24 h after d-serine administration. This suggests that the Cmax of d-serine could be a good predictor of d-serine-induced nephrotoxicity.

Introduction

The N-methyl-d-aspartate (NMDA) receptor, a type of glutamate receptor, plays important and indispensable roles in several higher brain functions such as learning, memory, and cognition [1]. NMDA receptor dysfunction has been hypothesized to play a role in the pathophysiology of schizophrenia [2].

d-Serine is present in the mammalian brain [3], and serves as an endogenous modulator of the glycine-binding site on NMDA receptors [[4], [5], [6], [7]]. Serum d-serine levels are significantly lower in patients with schizophrenia than in healthy subjects [8,9]. Since d-serine-mediated enhancement of NMDA receptor function may be beneficial in the treatment of schizophrenia, several clinical trials have tested the effects of d-serine supplementation in schizophrenia [[10], [11], [12], [13]]. In one of these trials, an oral d-serine dose of 30 mg/kg body weight (bw)/day (equivalent to 0.28 mmol/kg bw/day) significantly improved the positive, negative, and cognitive symptoms of schizophrenia. Although dose-dependent efficacy was observed at higher d-serine doses, one subject receiving d-serine at a dose of 120 mg/kg bw/day (1.1 mmol/kg bw/day) showed symptoms similar to those associated with nephrotoxicity [11]. At the same dose, the plasma concentration of d-serine was elevated up to approximately 500 nmol/ml, which is 200 times the physiological concentration.

Previous studies have revealed that d-serine is nephrotoxic in rats. High doses of d-serine cause necrosis in renal proximal tubules, with proteinuria and glucosuria in rats [[14], [15], [16], [17], [18], [19]]. d-Serine is not nephrotoxic in mice, guinea pigs, rabbits, dogs, and hamsters; however, the potential d-serine nephrotoxicity in humans remains unclear. To address concerns regarding the therapeutic usage of d-serine in humans, it is essential to clarify the mechanism underlying d-serine nephrotoxicity in rats and the plasma concentration at which d-serine induces renal injury. To determine the dose dependency of d-serine-induced nephrotoxicity in rats, Krug et al. [16] administered d-serine intraperitoneally (ip) and measured the consequent plasma concentrations of serine; however, the HPLC method they used could not separate d- from l-serine. Thus, minimal information is available on the plasma levels of d-serine that are associated with tubular necrosis in rats. In addition, no data exist on the plasma kinetics of d-serine in rats following oral administration; such data may provide information of d-serine kinetics in humans.

Recently, we developed a method for the stereoselective determination of serine enantiomers in biological fluids by using gas chromatography–mass spectrometry (GC–MS) with selecting ion monitoring (SIM) [20]. This method is based on a stable isotope dilution method, using stable isotope labeled dl-serine as an analytical standard, and a diastereomeric method, using (S)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride (MTPA-Cl) as a chiral derivatizing reagent.

The objective of the present study was to investigate the relationship between the plasma kinetics of d-serine and nephrotoxicity in rats.

Section snippets

Chemicals

d-Serine was purchased from Peptide Institute (Osaka, Japan). l-Serine was purchased from Wako Pure Chemicals (Osaka, Japan). dl-[2,3,3-2H3]Serine (dl-[2H3]serine, 98 atom % 2H) was purchased from Cambridge Isotope Laboratories (Andover, MA, USA). MTPA-Cl and 10% HCl in methanol were purchased from Tokyo Kasei (Tokyo, Japan). A strong cation-exchange solid-phase extraction column BondElut SCX (H+ form, size 1 ml/100 mg) was purchased from Agilent Technologies (Lake Forest, CA, USA). Chloroform

Pharmacokinetics of d-serine after iv, po, and ip administration

Following iv administration of d-serine (0.1 mmol/kg bw) to rats (n = 6), we measured the plasma concentration of d- and l-serine using the stable isotope dilution GCsingle bondMS method described previously [20]. The representative SIM profiles obtained from the plasma samples obtained before and 5 min after administration are shown in Fig. 1A and B, respectively. No substances other than d- and l-serine, and the labeled d- and l-serine were found in their monitoring ions. The plasma concentration of

Discussion

The most important advantage of stable isotope dilution analysis using a stable isotopically labeled analog as an internal standard is that the labeled analog behaves in an almost identical manner to the analyte throughout all steps in the extraction, derivatization, and chromatographic procedures. In this study, commercially available dl-[2H3]serine, which mimics d- and l-serine in plasma, was chosen as the internal standard. Therefore, if the extraction and/or derivatization processes were

Conclusion

In summary, in the present study, we elucidated the plasma kinetics of d-serine at therapeutic and high doses in rats. When the Cmax value of d-serine after ip administration exceeded approximately 2 μmol/ml, the plasma creatinine increased remarkably 24 h after administration, suggesting that Cmax of d-serine is a reliable predictor of d-serine-induced nephrotoxicity.

Declarations of interest

None.

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