Mora María J, Petiti Juan P, Longhi Marcela R, Torres Alicia I, Granero Gladys E
Departamento de Farmacia, UNITEFA, CONICET, Argentina.
Centro de Microscopía Electrónica, UNC, INICSA, CONICET, Argentina.
Int J Pharm. 2015 Jan 15;478(1):258-267. doi: 10.1016/j.ijpharm.2014.11.027. Epub 2014 Nov 13.
Large oral doses of ACZ lower the intraocular pressure (IOP), but usually lead to a multitude of systemic side effects, including gastrointestinal upset. The present study was undertaken to evaluate the effect of ACZ on the histological structure of rat duodenal mucosa and to assess a possible protective role of the complex formation of ACZ with HP-β-CD, either separately or in combination with a third compound, on the gut epithelial layer by histological and ultrastructural examinations of sections of rat duodenum exposed to ACZ or its formulations. In addition, the transport process of ACZ and its binary or ternary complexes across the duodenal mucosa by means of the single-pass intestinal perfusion (SPIP) method in rats was evaluated. Evidence was found that ACZ alters intestinal permeability and induces damage to the rat small intestine. In contrast, ACZ-induced intestinal injury may be abrogated by ACZ complexation. In addition, the complexation of ACZ with HP-β-CD, alone or in combination with a third compound, facilitated significant levels of ACZ uptake across the rat duodenal segment. Ternary complexes of ACZ with HP-β-CD in combination with TEA (triethanolamine) or calcium ions were found to provide an excellent approach that enabled an increased apparent permeability of ACZ across the duodenal epithelium, with a concomitant ability to preserve the integrity of the gut epithelium from ACZ-induced injury. These results could be useful for the design and development of novel ACZ formulations that can reduce GI toxicity, while still maintaining their essential therapeutic efficacies.
大剂量口服乙酰唑胺可降低眼压（IOP），但通常会引发多种全身副作用，包括胃肠道不适。本研究旨在通过对暴露于乙酰唑胺或其制剂的大鼠十二指肠切片进行组织学和超微结构检查，评估乙酰唑胺对大鼠十二指肠黏膜组织结构的影响，并评估乙酰唑胺与羟丙基-β-环糊精单独或与第三种化合物形成复合物对肠道上皮层的可能保护作用。此外，还通过大鼠单通道肠灌注（SPIP）法评估了乙酰唑胺及其二元或三元复合物在十二指肠黏膜的转运过程。研究发现，乙酰唑胺会改变肠道通透性并导致大鼠小肠损伤。相比之下，乙酰唑胺诱导的肠道损伤可通过乙酰唑胺络合消除。此外，乙酰唑胺与羟丙基-β-环糊精单独或与第三种化合物形成复合物，促进了乙酰唑胺在大鼠十二指肠段的显著摄取。发现乙酰唑胺与羟丙基-β-环糊精与三乙醇胺（TEA）或钙离子形成的三元复合物提供了一种极佳的方法，能够提高乙酰唑胺在十二指肠上皮的表观通透性，同时具有保护肠道上皮免受乙酰唑胺诱导损伤的完整性的能力。这些结果可能有助于设计和开发新型乙酰唑胺制剂，既能降低胃肠道毒性，又能保持其基本治疗效果。
