Dahlgren David, Olander Tobias, Sjöblom Markus, Hedeland Mikael, Lennernäs Hans
Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala 752 36, Sweden.
Department of Neuroscience, Division of Physiology, Uppsala University, Uppsala 752 36, Sweden.
Acta Pharm Sin B. 2021 Jun;11(6):1667-1675. doi: 10.1016/j.apsb.2020.12.019. Epub 2021 Jan 5.
Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of chromium-labeled EDTA (CL), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of Cr-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.
已知跨细胞渗透增强剂可增加依那普利拉（一种349道尔顿的肽）的肠道通透性，但对生长激素释放六肽（887道尔顿）无效。本文的主要目的是研究细胞旁渗透增强剂是否会影响这两种肽的肠道渗透。这是通过大鼠单通道肠道灌注模型并同时采集血液样本进行研究的。这些肠腔成分包括两种细胞旁渗透增强剂，壳聚糖（5毫克/毫升）和乙二胺四乙酸（EDTA，1和5毫克/毫升），以及低肠腔张力（100毫渗量），添加或不添加利多卡因。通过生长激素释放六肽和依那普利拉的肠腔到血液的通透性变化以及铬标记的EDTA（CL，一种黏膜屏障完整性的临床标志物）的血液到肠腔清除率来评估效果。这两种细胞旁渗透增强剂使两种肽类药物的黏膜通透性增加程度相似。本研究中的数据表明，细胞旁渗透增强剂增加低分子量亲水性肽肠道吸收的潜力大于具有跨细胞作用机制的肽。此外，两种细胞旁渗透增强剂和肠腔低渗性均增加了Cr-EDTA的黏膜血液到肠腔通量。相比之下，肠腔低渗性不影响依那普利拉和生长激素释放六肽的肠腔到血液转运。这表明低渗性主要影响黏膜隐窝区域的细胞旁溶质转运，因为该区域通过隐窝持续的水流免受肠腔内容物的影响。
