Transmembrane transport of peptide type compounds: Prospects for oral delivery
Transmembrane transport of peptide type compounds: Prospects for oral delivery
复制标题
DOI：
10.1016/0168-3659(95)00145-x
复制
发表时间：
1996-05-01
影响因子：
10.8
通讯作者：
Amidon, GL
中科院分区：
文献类型：
--
作者：
Lipka, E;Crison, J;Amidon, GL
潜在治疗性肽和拟肽化合物的合成和递送一直是过去 10 年来深入研究的焦点，虽然人们普遍认识到肽的口服递送存在许多限制，但一些限制因素已经得到解决，其机制也已得到阐明，从而产生了有希望的策略。本文将简要总结口服肽递送的挑战、结果和当前方法，并对未来策略提出一些见解。口服给药后决定肽生物利用度的障碍是肠膜渗透性、大小限制、肠和肝代谢以及在某些情况下溶解度限制。亲水肽的膜渗透性差可以通过对化合物进行结构修饰来克服，从而增加它们的膜分区特性和/或它们对载体蛋白的亲和力。另一种方法是将肽定点递送至肠道最具渗透性的部分。当前关于口服药物递送尺寸限制的观点忽略了分区考虑。最近的研究表明，假设适当的分配行为和稳定性，分子量高达 4000 的化合物可能会被显着吸收。代谢可能是肽吸收命运中最重要的因素，可以通过竞争性酶抑制剂的共同给药、结构修饰以及将化合物作为吸收良好的前药给药来控制，该前药在吸收后转化为治疗活性剂。对于某些肽，溶解度差可能会限制口服吸收，这一问题已通过机械定义并因此改进配方参数得到解决。有效的口服肽递送需要进一步了解这些复杂的机制，以便最大限度地发挥此类化合物的治疗潜力。
Synthesis and delivery of potential therapeutic peptides and peptidomimetic compounds has been the focus of intense research over the last 10 years, While it is widely recognized that numerous limitations apply to oral delivery of peptides, some of the limiting factors have been addressed and their mechanisms elucidated, which has lead to promising strategies. This article will briefly summarize the challenges, results and current approaches of oral peptide delivery and give some insight on future strategies. The barriers determining peptide bioavailability after oral administration are intestinal membrane permeability, size limitations, intestinal and hepatic metabolism and in some cases solubility Limitations. Poor membrane permeabilities of hydrophilic peptides might be overcome by structurally modifying the compounds, thus increasing their membrane partition characteristics and/or their affinity to carrier proteins. Another approach is the site-specific delivery of the peptide to the most permeable parts of the intestine. The current view on size limitation for oral drug delivery has neglected partition considerations. Recent studies suggest that compounds with a molecular weight up to 4000 might be significantly absorbed, assuming appropriate partition behavior and stability. Metabolism, probably the most significant factor in the absorption fate of peptides, might be controlled by coadministration of competitive enzyme inhibitors, structural modifications and administration of the compound as a well absorbed prodrug that is converted into the therapeutically active agent after its absorption. For some peptides poor solubility might present a limitation to oral absorption, an issue that has been addressed by mechanistically defining and therefore improving formulation parameters. Effective oral peptide delivery requires further development in understanding these complex mechanisms in order to maximize the therapeutic potential of this class of compounds.