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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：姜黄素前体药物姜黄素二丁二酸二乙酯水解激活涉及的稳定性动力学和血浆酯酶的种间差异

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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：酯前药的体外血浆代谢研究是临床前药物开发过程中体外ADME测定的重要组成部分。在这里，我们显示了在狗和人血浆中的体外代谢，包括血浆稳定性和姜黄素二琥珀酸姜黄素二乙酯（CDD）（姜黄素的酯前药）的体外代谢和相似，但与大鼠血浆中的代谢明显不同。 HPLC和非线性回归分析表明，血浆中CDD的水解遵循连续的伪一级反应。血浆酯酶按以下顺序加速了CDD在大鼠，狗和人血浆中的快速水解。人>狗。 LC-Q-TOF / MS分析表明，CDD酯键的裂解优先于酚酯。在所有被测物种中，单乙基琥珀酰姜黄素是CDD血浆代谢中发现的唯一中间代谢物。使用不同的酯酶抑制剂的进一步研究表明，羧酸酯酶是参与大鼠CDD水解的主要酶，而多种血浆酯酶则在犬和人中发挥作用。因此，此处观察到的大鼠，狗和人血浆中CDD代谢的水解速率和代谢酶的差异有利于进一步的体内研究，并为设计具有酯酶特异性生物激活作用的CUR酯前药提供了理论依据。

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