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首页> 外文期刊>RSC Advances >Interspecies differences in stability kinetics and plasma esterases involved in hydrolytic activation of curcumin diethyl disuccinate, a prodrug of curcumin
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Interspecies differences in stability kinetics and plasma esterases involved in hydrolytic activation of curcumin diethyl disuccinate, a prodrug of curcumin

机译：静止动力学和血浆酯酶的差异差异参与姜黄素二乙酯的水解活化，一种姜黄素前药

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摘要

The investigation of in vitro plasma metabolism of ester prodrugs is an important part of in vitro ADME assays during preclinical drug development. Here, we show that the in vitro metabolism including plasma stability and metabolizing enzymes of curcumin diethyl disuccinate (CDD), an ester prodrug of curcumin, in dog and human plasma are similar but markedly different from those in rat plasma. HPLC and nonlinear regression analyses indicated that the hydrolysis of CDD in plasma followed a consecutive pseudo-first order reaction. The rapid hydrolytic cleavage of CDD in rat, dog, and human plasma was accelerated by plasma esterases in the following order: rat human dog. LC-Q-TOF/MS analysis showed that the cleavage of ester bonds of CDD is preferential at the phenolic ester. Monoethylsuccinyl curcumin is the only intermediate metabolite found in plasma metabolism of CDD in all tested species. Further investigation using different esterase inhibitors revealed that carboxylesterase is the major enzyme involved in the hydrolysis of CDD in rats while multiple plasma esterases play a role in dogs and humans. Thus, the difference in the hydrolysis rates and the metabolizing enzymes of CDD metabolism in rat, dog and human plasma observed here is of benefit to further in vivo studies and provides a rationale for designing ester prodrugs of CUR with esterase-specific bioactivation.
机译：酯前药物体外血浆代谢的研究是临床前药物发育中体外Adme测定的重要组成部分。在这里，我们表明，在包括血浆稳定性和姜黄素二乙基四氟乙酯（CDD）的代谢酶，柠檬蛋白，柠蛋白，柠檬蛋白，在狗和人血浆中的体外代谢具有类似但与大鼠等离子体中的那些类似但显着不同。 HPLC和非线性回归分析表明，血浆中CDD的水解遵循连续的伪第一阶反应。在以下顺序中，血浆酯酶加速了大鼠，狗和人血浆中CDD的快速水解切割：RAT＆GT;＆GT;人和狗。 LC-Q-TOF / MS分析表明，CDD的酯键的切割优先于酚酯。单乙基琥珀基姜黄素是所有测试物种中CDD的血浆代谢中唯一唯一的中间代谢物。使用不同酯酶抑制剂的进一步研究表明，羧基酯酶是在大鼠中涉及CDD水解的主要酶，而多个血浆酯酶在狗和人类中起作用。因此，在这里观察到的大鼠，狗和人血浆中的水解率和CDD代谢的代谢酶的差异是有益的，进一步在体内研究中进一步有益，并提供了用酯酶特异性生物活化设计Cur的酯前药的理由。

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