Univerisity of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
J Pharm Sci. 2011 Mar;100(3):1184-95. doi: 10.1002/jps.22332. Epub 2010 Sep 16.
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 μM) 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.
加巴喷丁是一种两性离子药物，在治疗剂量下表现出低且可变的口服吸收。人顶端钠依赖性胆汁酸转运体（hASBT；SLC10A2）是增加口服药物吸收的潜在前药靶点。目的是评估几种加巴喷丁的胆汁酸缀合物作为靶向 hASBT 的潜在前药。合成了 5 种类似物，并在离子性质和药物与胆汁酸之间是否存在谷氨酸接头方面进行了变化。使用稳定转染的 hASBT-MDCK 细胞评估类似物的抑制和摄取特性。两种单阴离子缀合物是强效的 hASBT 底物，具有高亲和力（K(m)分别为 16.3 和 5.99 μM）和高容量（V(max)分别为 0.656 和 0.842 pmol/cm(2) /s）。二价阴离子缀合物对 hASBT 的抑制作用具有中等效力，但不是底物。两种单阴离子缀合物在 Caco-2 匀浆和大鼠肝微粒体中均发生催化降解。每个产物均从前药中生成加巴喷丁。这两种缀合物是加巴喷丁的新型前药，并说明了可以设计用于靶向 hASBT 的前药。
