Pharmacokinetics and cerebral distribution of glycine administered to rats
Pharmacokinetics and cerebral distribution of glycine administered to rats
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DOI：
10.1007/s00726-011-0950-y
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发表时间：
2012-06-01
期刊：
影响因子：
3.5
通讯作者：
Shimizu, Eiji
中科院分区：
文献类型：
--
作者：
Kawai, Nobuhiro;Bannai, Makoto;Shimizu, Eiji
据报道，高剂量的甘氨酸可改善阴性精神分裂症症状，这表明摄入的甘氨酸可通过-甲基-天冬氨酸（NMDA）受体激活谷氨酸能传递。然而，给药的甘氨酸在大脑中的药代动力学尚未得到评估。在本研究中，从药代动力学的角度研究了给药甘氨酸的时间和剂量依赖性分布。对放射标记的甘氨酸进行全身放射自显影，获得血浆、脑脊液（CSF）和脑组织中甘氨酸和丝氨酸的时间-浓度曲线。并计算药代动力学参数。为了进行更详细的分析，使用脑摄取指数法评估脑中甘氨酸的摄取量。放射标记的甘氨酸分布于脑室周围器官。口服2 g/kg甘氨酸可显著提高脑脊液甘氨酸浓度，高于NMDA受体的ED50值。脑脊液中甘氨酸水平比血浆低100倍。脑组织中甘氨酸水平升高，但时间过程比脑脊液慢。血浆、脑脊液和脑组织中甘氨酸的主要代谢物丝氨酸升高。脑组织中甘氨酸的摄取以剂量依赖的方式增加。时间-浓度曲线显示甘氨酸很可能通过血- csf屏障转运，激活脑室附近的NMDA受体。药代动力学分析和甘氨酸脑摄取指数表明甘氨酸通过被动扩散进入脑组织。这些结果为甘氨酸的潜在治疗应用提供了进一步的见解。
High doses of glycine have been reported to improve negative schizophrenic symptoms, suggesting that ingested glycine activates glutamatergic transmission via -methyl--aspartate (NMDA) receptors. However, the pharmacokinetics of administered glycine in the brain has not been evaluated. In the present study, the time- and dose-dependent distributions of administered glycine were investigated from a pharmacokinetic viewpoint. Whole-body autoradiography of radiolabeled glycine was performed, and time-concentration curves for glycine and serine in plasma, cerebrospinal fluid (CSF), and brain tissues were obtained. Furthermore, pharmacokinetic parameters were calculated. For a more detailed analysis, the amount of glycine uptake in the brain was evaluated using the brain uptake index method. Radiolabeled glycine was distributed among periventricular organs in the brain. Oral administration of 2 g/kg of glycine significantly elevated the CSF glycine concentration above the ED50 value for NMDA receptors. The glycine levels in CSF were 100 times lower than those in plasma. Glycine levels were elevated in brain tissue, but with a slower time-course than in CSF. Serine, a major metabolite of glycine, was elevated in plasma, CSF, and brain tissue. Glycine uptake in brain tissue increased in a dose-dependent manner. Time-concentration curves revealed that glycine was most likely transported via the blood-CSF barrier and activated NMDA receptors adjacent to the ventricles. The pharmacokinetic analysis and the brain uptake index for glycine suggested that glycine was transported into brain tissue by passive diffusion. These results provide further insight into the potential therapeutic applications of glycine.