N-Acetylcysteine ethyl ester (NACET): A novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential
N-Acetylcysteine ethyl ester (NACET): A novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential
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DOI：
10.1016/j.bcp.2012.09.010
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发表时间：
2012-12-01
影响因子：
5.8
通讯作者：
Rossi, Ranieri
中科院分区：
文献类型：
--
作者：
Giustarini, Daniela;Milzani, Aldo;Rossi, Ranieri
最近的大型临床试验未能证实 N-乙酰半胱氨酸 (NAC) 在预防氧化应激相关疾病方面的有益作用。这可能是由于其生物利用度低。我们认为，NAC的羧基酯化产生N-乙酰半胱氨酸乙酯（NACET）会大大增加NAC的亲脂性，从而大大改善其药代动力学。在本工作中，我们报告了NACET的代表性化学、药理学和抗氧化特性，特别是与其同类NAC直接比较。我们发现 NACET 口服后在大鼠体内迅速吸收，但在血浆中达到非常低的浓度。这是由于 NACET 的一个独特特征：它快速进入细胞并被捕获并转化为 NAC 和半胱氨酸。口服治疗后，NACET（但不是 NAC）能够显着增加大多数检查组织（包括大脑）的谷胱甘肽含量，并防止大鼠出现扑热息痛中毒。 NACET 还具有在人红细胞中积累的独特功能，可作为有效的保护剂，防止氢过氧化物引起的氧化损伤。我们的研究表明，NACET 能够进入细胞并产生 NAC 和半胱氨酸，可增加循环中的硫化氢 (H2S)，因此是口服使用的 H2S 产生剂的良好候选者，与 NAC 相比具有明显的优势。NACET 有潜力替代 NAC 作为粘液溶解剂、扑热息痛解毒剂和 GSH 相关抗氧化剂。 (C) 2012 Elsevier Inc. 保留所有权利。
Recent large clinical trials failed to confirm the supposed beneficial effects of N-acetylcysteine (NAC) in preventing oxidative stress-related diseases. This may be due to its low bioavailability. We thought that esterification of the carboxyl group of NAC to produce N-acetylcysteine ethyl ester (NACET) would drastically increase the lipophilicity of NAC, thus greatly improving its pharmacokinetics.In the present work, we report on representative chemical, pharmacological and anti-oxidant properties of NACET, especially in direct comparison with its congener NAC. We found that NACET is rapidly absorbed in rats after oral administration but reaches very low concentrations in plasma. This is due to a unique feature of NACET: it rapidly enters the cells where it is trapped being transformed into NAC and cysteine. After oral treatment, NACET (but not NAC) was able to increase significantly the glutathione content of most tissues examined, brain included, and to protect from paracetamol intoxication in the rat. NACET has also the unique feature to accumulate in human erythrocytes where it behaves as a potent protector against hydroperoxide-induced oxidative damage. Our study shows that being able to enter cells and to produce NAC and cysteine, NACET increases circulating hydrogen sulfide (H2S), thus representing a good candidate for the oral use as an H2S producer, with clear advantages over NAC.NACET has the potential to substitute NAC as a mucolytic agent, as a paracetamol antidote and as a GSH-related antioxidant. (C) 2012 Elsevier Inc. All rights reserved.