HIGH-DOSE INTRAVENOUS GLUTATHIONE IN MAN - PHARMACOKINETICS AND EFFECTS ON CYST(E)INE IN PLASMA AND URINE
HIGH-DOSE INTRAVENOUS GLUTATHIONE IN MAN - PHARMACOKINETICS AND EFFECTS ON CYST(E)INE IN PLASMA AND URINE
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DOI：
10.1111/j.1365-2362.1991.tb01366.x
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发表时间：
1991-02-01
影响因子：
5.5
通讯作者：
LAUTERBURG, BH
中科院分区：
文献类型：
--
作者：
AEBI, S;ASSERETO, R;LAUTERBURG, BH
胃肠外谷胱甘肽具有靶向递送半胱氨酸等效物的治疗潜力。因此，高剂量的还原型谷胱甘肽（GSH）可保护肾免受顺铂和氧氮磷的肾毒性和尿毒性作用。为了阐明谷胱甘肽对血浆和尿中巯基的影响及其动力学机制，在10名健康志愿者中进行了研究。静脉输注2 g m-2谷胱甘肽后，血浆中总谷胱甘肽的浓度从17.5 +/- 13.4-mu-mol l-1（平均值+/- SD）增加至823 +/- 326-mu-mol l-1。外源性谷胱甘肽的分布容积为176 +/- 107 ml kg-1，消除速率常数为0.063 +/- 0.027 min-1，对应于14.1 +/- 9.2 min的半衰期。输注后，血浆中的半胱氨酸从8.9 +/- 3.5-mu-mol l-1增加到114 +/- 45-mu-mol l-1。尽管半胱氨酸增加，但总半胱氨酸（即半胱氨酸、胱氨酸和混合二硫化物）的血浆浓度降低，表明细胞从血浆中摄取的半胱氨酸增加。在输注后90分钟内，谷胱甘肽和胱氨酸的尿排泄分别增加了300倍和10倍。目前的数据表明，在尿路中的sulphydryls的浓度，更重要的是，细胞内的半胱氨酸的利用率显着增加胃肠外谷胱甘肽。细胞内高浓度的半胱氨酸可以直接或间接地通过支持谷胱甘肽的合成来防止顺铂和氧氮磷杂环丁烷的毒性。
Parenteral glutathione has therapeutic potential for targeted delivery of cysteine equivalents. Thus, high doses of reduced glutathione (GSH) protect from the nephrotoxic and urotoxic effects of cisplatinum and oxazaphosphorines. In order to elucidate the underlying mechanisms the kinetics and the effect of glutathione on plasma and urine sulphydryls were studied in 10 healthy volunteers. Following the intravenous infusion of 2 g m-2 of glutathione the concentration of total glutathione in plasma increased from 17.5 +/- 13.4-mu-mol l-1 (mean +/- SD) to 823 +/- 326-mu-mol l-1. The volume of distribution of exogenous glutathione was 176 +/- 107 ml kg-1 and the elimination rate constant was 0.063 +/- 0.027 min-1 corresponding to a half-life of 14.1 +/- 9.2 min. Cysteine in plasma increased from 8.9 +/- 3.5-mu-mol l-1 to 114 +/- 45-mu-mol l-1 after the infusion. In spite of the increase in cysteine, the plasma concentration of total cyst(e)ine (i.e. cysteine, cystine, and mixed disulphides) decreased, suggesting an increased uptake of cysteine from plasma into cells. Urinary excretion of glutathione and of cyst(e)ine was increased 300-fold and 10-fold, respectively, in the 90 min following the infusion. The present data suggest that the concentration of sulphydryls in the urinary tract and, more importantly, the intracellular availability of cysteine increase markedly following parenteral glutathione. The high intracellular concentration of cysteine may protect against cisplatinum and oxazaphosphorine toxicity either directly or indirectly by supporting the synthesis of glutathione.