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首页> 外文期刊>Journal of pharmaceutical sciences. >Synthesis and in vitro evaluation of gabapentin prodrugs that target the human apical sodium-dependent bile acid transporter (hASBT).
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Synthesis and in vitro evaluation of gabapentin prodrugs that target the human apical sodium-dependent bile acid transporter (hASBT).

机译：靶向人类根尖钠依赖性胆汁酸转运蛋白（hASBT）的加巴喷丁前药的合成和体外评估。

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摘要

Gabapentin is a zwitterionic drug that exhibits low and variable oral absorption at therapeutic doses. The human apical sodium-dependent bile acid transporter (hASBT; SLC10A2) is a potential prodrug target to increase oral drug absorption. The objective was to evaluate several bile acid conjugates of gabapentin as potential prodrugs that target hASBT. Five analogues were synthesized and varied in ionic nature and the presence or absence of glutamic acid linker between the bile acid and drug. Analogues were evaluated for their inhibition and uptake properties using stably transfected hASBT-MDCK cells. The two monoanionic conjugates were potent hASBT substrates, with high affinity (K(m) of 16.3 and 5.99 muM) and high capacity (V(max) of 0.656 and 0.842 pmol/cm(2) /s). The dianionic conjugate inhibited hASBT with moderate potency but was not a substrate. The two monoanionic conjugates were catalytically degraded in Caco-2 homogenate and rat liver microsomes. Each yielded gabapentin from prodrug. These two conjugates are novel prodrugs of gabapentin and illustrate prodrugs that can be designed to target hASBT.
机译：加巴喷丁是一种两性离子药物，在治疗剂量下口服吸收低而可变。人类根尖钠依赖性胆汁酸转运蛋白（hASBT; SLC10A2）是增加口服药物吸收的潜在前药靶标。目的是评估加巴喷丁的几种胆汁酸缀合物作为靶向hASBT的潜在前药。合成了五个类似物，它们的离子性质以及在胆汁酸和药物之间是否存在谷氨酸连接基的情况都不同。使用稳定转染的hASBT-MDCK细胞评估类似物的抑制和摄取特性。两种单阴离子共轭物是有效的hASBT底物，具有高亲和力（K（m）为16.3和5.99μM）和高容量（V（max）为0.656和0.842 pmol / cm（2）/ s）。双阴离子共轭物以中等效力抑制hASBT，但不是底物。两种单阴离子共轭物在Caco-2匀浆和大鼠肝微粒体中被催化降解。每个人都从前药中产生加巴喷丁。这两种结合物是加巴喷丁的新型前药，并说明了可设计用于靶向hASBT的前药。

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