Pharmacokinetics and toxicokinetics of D-serine in rats
Pharmacokinetics and toxicokinetics of D-serine in rats
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DOI：
10.1016/j.jpba.2018.09.026
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发表时间：
2019-01-05
影响因子：
3.4
通讯作者：
Ichida, Kimiyoshi
中科院分区：
文献类型：
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作者：
Hasegawa, Hiroshi;Masuda, Nami;Ichida, Kimiyoshi
在哺乳动物脑中，D-丝氨酸在N-甲基-D-天冬氨酸受体上的甘氨酸结合位点处作为共激动剂。由于精神分裂症患者的血浆D-丝氨酸水平显著低于健康受试者，因此D-丝氨酸已被提议作为精神分裂症治疗的潜在治疗剂。然而，D-丝氨酸在高剂量下对大鼠具有肾毒性作用。本研究旨在探讨D-丝氨酸在大鼠体内的血浆动力学与肾毒性的关系。我们给D-丝氨酸静脉注射（iv），口服（po），或腹腔注射（ip）给雄性Wistar大鼠，并进行气相色谱-质谱法测定血浆中的D-和L-丝氨酸浓度。静脉给药（0.1 mmol/kg体重（bw））后，血浆D-丝氨酸呈多指数下降，消除t（1/2）为108 +/- 16 min，总清除率为7.9 +/- 0.9 ml/min/kg bw。D-丝氨酸的口服生物利用度估计为94 +/-27%。为了评价D-丝氨酸诱导的肾损伤的剂量-反应关系和D-丝氨酸的血浆动力学，我们将D-丝氨酸以0.6至4.8 mmol/kg bw的剂量注射到大鼠中。D-丝氨酸给药后24小时，在接受1.8-4.8 mmol/kg bw剂量D-丝氨酸的大鼠肾脏中观察到表明肾损伤的组织学变化;肾小管损伤的严重程度随着D-丝氨酸剂量的增加而增加。当D-丝氨酸的C-max值约>2 μ mol/ml时，D-丝氨酸给药后24小时血浆肌酐显著升高。这表明D-丝氨酸的C-max可以是D-丝氨酸诱导的肾毒性的良好预测因子。(C)2018爱思唯尔B. V.保留所有权利。
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.