Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist
Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist
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DOI：
10.1126/scitranslmed.aar7047
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发表时间：
2018-11-14
影响因子：
17.1
通讯作者：
Knudsen, Lotte Bjerre
中科院分区：
文献类型：
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作者：
Buckley, Stephen T.;Baekdal, Tine A.;Knudsen, Lotte Bjerre
治疗性肽的口服给药由于穿过胃肠屏障的吸收差和蛋白水解酶的广泛降解而受阻。在此，我们研究了口服semaglutide（一种胰高血糖素样肽-1类似物）与吸收促进剂N-[8-（2-羟基苯甲酰基）氨基辛酸钠]（SNAC）联合配制的片剂的吸收。与小分子通常观察到的肠道吸收相反，临床和临床前犬研究显示，Semaglutide的吸收发生在胃中，仅限于靠近片剂表面的区域，并且需要与SNAC共制剂。SNAC通过局部缓冲作用防止酶降解，并且仅短暂增强吸收。吸收机制显示为化合物特异性、跨细胞，且无任何证据表明对紧密连接有影响。这些数据对于理解高效和特异性治疗肽如何从注射剂转化为基于片剂的口服疗法具有意义。
Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.