Laboratory of Bio-Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
Adv Drug Deliv Rev. 2012 May 1;64(6):515-22. doi: 10.1016/j.addr.2011.07.004. Epub 2011 Jul 23.
Epithelium covers the body and, therefore, separates the inner body from the outside environment. Passage across the epithelium is the first step in drug absorption. Tight junctions (TJs) seal the space between adjacent epithelial cells and prevent the free movement of solutes through the paracellular space. Modulation of the epithelial barrier is the most important strategy for enhancing drug absorption. Development of the strategy has accelerated with progress in understanding of the biology of the TJ seal. The first-generation absorption enhancers were screened on the basis of their absorption-enhancing activity in vivo. However, TJs were not well understood initially. The identification of TJ components, including those based on occludin and claudins, has led to the development of new strategies for drug absorption. Accumulation of knowledge of claudins has provided new insights into the paracellular transport of drugs. This review examines the relationship between advances in understanding of TJ biology and paracellular transport of drugs and discusses progress in the development of mucosal absorption enhancers.
上皮组织覆盖于人体表面，将体内与外界环境分隔开来。药物的吸收首先要穿过上皮组织。紧密连接（Tight junctions，TJ）将相邻上皮细胞间的间隙封闭起来，防止溶质经细胞旁途径自由扩散。调节上皮屏障功能是增强药物经黏膜吸收的重要策略。随着对 TJ 封闭机制的深入了解，该策略的发展得以加速。第一代吸收促进剂是根据其在体内的促吸收活性筛选出来的。然而，最初人们对 TJ 的了解并不充分。随着对包括闭合蛋白（occludin）和紧密连接蛋白（claudin）在内的 TJ 组成成分的鉴定，促进药物吸收的新策略也随之产生。对紧密连接蛋白的认识不断深入，为药物经细胞旁途径转运提供了新的见解。本文综述了 TJ 生物学和药物经细胞旁途径转运研究进展之间的关系，并讨论了黏膜吸收促进剂的开发进展。
