Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models
Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models
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DOI：
10.1002/bdd.1950
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发表时间：
2015-09-01
影响因子：
2.1
通讯作者：
Mandlekar, Sandhya
中科院分区：
文献类型：
--
作者：
Holenarsipur, Vinay K.;Gaud, Nilesh;Mandlekar, Sandhya
近年来，前药策略已被广泛用于改善生物利用度差的化合物的药代动力学性质。对口服前药的吸收机制以及肠和肝在活化中的作用的理解至关重要。依那普利是一种羧基酯前药，据报道可通过人羧酸酯酶-1（CES 1）代谢，但不通过羧酸酯酶-2（CES 2）代谢为活性代谢物依那普利拉。此外，据报道，大鼠和人的小肠主要含有CES 2。这项工作的目的是了解依那普利是否保持不变，因为它是通过肠道吸收到门静脉循环。这是评价使用不同的肠道准备，在原位肠灌注实验和门静脉插管大鼠模型。商业大鼠肠道S9和微粒体中未观察到依那普利的周转，但新鲜制备的大鼠肠道和粘膜匀浆和S9中观察到合理的周转。在肠灌注研究中，在肠系膜血浆中观察到依那普利和依那普利拉，数据表明依那普利在肠中水解32%。在门静脉插管大鼠，约51%的依那普利吸收到肠道转化为依那普利拉。总体而言，已经证明，即使依那普利已被证明是CES 1的特异性底物，但它在肠道中被转化为依那普利拉的程度很大。这些实验技术可以被其他研究前药的科学小组应用，以确定激活的区域和程度。版权所有（c）2015约翰威利父子有限公司
In recent years prodrug strategy has been used extensively to improve the pharmacokinetic properties of compounds exhibiting poor bioavailability. Mechanistic understanding of the absorption and the role of intestine and liver in the activation of oral prodrugs is crucial. Enalapril, a carboxyl ester prodrug, is reported to be metabolized by human carboxylesterase-1 (CES1) but not by carboxylesterase-2 (CES2) to its active metabolite enalaprilat. Further, it has been reported that the small intestines of both rat and human contain mainly CES2. The objective of this work was to understand whether enalapril remains unchanged as it is absorbed through the intestine into the portal circulation. This was evaluated using different intestinal preparations, an in situ intestinal perfusion experiment and a portal vein cannulated rat model. No turnover of enalapril was seen with commercial rat intestinal S9 and microsomes, but reasonable turnover was observed with freshly prepared rat intestinal and mucosal homogenate and S9. In the intestinal perfusion study, both enalapril and enalaprilat were observed in the mesenteric plasma with the data suggesting 32% hydrolysis of enalapril in the intestine. In the portal vein cannulated rat, about 51% of enalapril absorbed into intestine was converted to enalaprilat. Overall, it was demonstrated that even though enalapril has been shown to be a specific substrate for CES1, it is converted to enalaprilat to a significant extent in the intestine. Such experimental techniques can be applied by other scientific groups who are working on prodrugs to determine the region and extent of activation. Copyright (c) 2015 John Wiley & Sons, Ltd.