Identification of major esterase involved in hydrolysis of soft anticholinergic (2R3’R-SGM) designed from glycopyrrolate in human and rat tissues
Identification of major esterase involved in hydrolysis of soft anticholinergic (2R3’R-SGM) designed from glycopyrrolate in human and rat tissues
复制标题
鉴定人和大鼠组织中参与由格隆溴铵设计的软抗胆碱能药物 (2R3’R-SGM) 水解的主要酯酶
DOI：
10.1016/j.xphs.2019.03.030
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发表时间：
2019
影响因子：
3.8
通讯作者：
Teruko Imai
中科院分区：
文献类型：
--
作者：
Ahmed Samir;Kayoko Ohura;Nicholas Bodor;Teruko Imai
格隆溴铵软性类似物SGM被设计为易于水解成活性显著较低的两性离子代谢物SGa，其代表了在局部给药后减少全身副作用（传统抗胆碱能药物常见的问题）的软性药物。在这项研究中，水解的2 R3 'R-SGM，最高的手性立体异构体的SGM，在人类和大鼠组织进行了研究。在这两个物种中，2 R3 'R-SGM在血浆中代谢为2 R3' R-SGa，但在肝脏和肠道中稳定。发现2 R3 ′ R-SGM在人和大鼠血浆中的半衰期分别为16.9 min和9.8 min。酶抑制和刺激实验表明，人和大鼠血浆对氧磷酶1（PON 1）参与2 R3 ′ R-SGM的水解。PON 1介导的2 R3 'R-SGM水解在人血浆的富脂蛋白组分中得到证实。由于PON 1天然附着于高密度脂蛋白，因此在应用2 R3 ′ R-SGM的局部组织中可能不存在PON 1，这支持其局部稳定性和疗效。2 R3 ′ R-SGM的代谢行为表明，它是一种理想的软性药物，进入体循环后即被解毒。此外，人和大鼠中2 R3 'R-SGM代谢的相似性表明大鼠是临床前研究的合适动物。
The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2R3’R-SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2R3’R-SGM was metabolized to 2R3’R-SGa in plasma but was stable in liver and intestine. The half-life of 2R3’R-SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2R3’R-SGM in humans and rats. The PON1-mediated hydrolysis of 2R3’R-SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2R3’R-SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2R3’R-SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2R3’R-SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study.