Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical and Health Science Center, University of Debrecen, H-4010 Debrecen, Hungary.
J Pharm Sci. 2011 Nov;100(11):4734-44. doi: 10.1002/jps.22666. Epub 2011 Jun 9.
Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated β-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated β-cyclodextrin (RAMEB) is cytotoxic in high concentrations. Second-generation derivatives containing monoamino (MaRAMEB) and succinylated (SuRAMEB) ionic substituents with similar inclusion capacity but less toxicity could be promising alternatives of RAMEB. Our aim was to examine and compare the efficacy of MaRAMEB and SuRAMEB with the parental RAMEB on taxol bidirectional permeability using the Caco-2 model. Taxol permeability was not changed by 30-min pretreatment with CDs. In co-treatment with β-cyclodextrins, the apical to basolateral taxol flux was 4 to 6 times greater than in untreated monolayers and it was also higher than in cells treated with Pgp inhibitor cyclosporin A. No decrease in basolateral to apical taxol flux was observed in pretreatment or co-treatment with CDs, suggesting no Pgp inhibition. All three CDs showed similar effects on taxol permeability but RAMEB altered tight junction protein distribution and significantly decreased transepithelial electrical resistance. None of the CDs modified paracellular permeability to mannitol and polyethylene glycol 4000. In conclusion, second-generation derivatives of methyl-β-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB.
紫杉醇的肠道吸收和生物利用度受到其低溶解度和 P-糖蛋白（Pgp）活性的限制。甲基-β-环糊精（CDs）可有效地与紫杉醇形成复合物，但高浓度的随机甲基-β-环糊精（RAMEB）具有细胞毒性。含有单氨基（MaRAMEB）和琥珀酰化（SuRAMEB）离子取代基的第二代衍生物具有相似的包合能力，但毒性较小，可能是 RAMEB 的有前途的替代品。我们的目的是使用 Caco-2 模型研究并比较 MaRAMEB 和 SuRAMEB 与亲本 RAMEB 对紫杉醇双向渗透性的效果。30 分钟的 CD 预处理不会改变紫杉醇的通透性。在用β-环糊精共同处理时，紫杉醇的顶端到基底外侧的通量是未经处理的单层的 4 到 6 倍，也高于用 Pgp 抑制剂环孢素 A 处理的细胞。在预处理或与 CD 共同处理时，未观察到基底外侧到顶端的紫杉醇通量下降，表明没有 Pgp 抑制。所有三种 CD 对紫杉醇的通透性均具有相似的影响，但 RAMEB 改变了紧密连接蛋白的分布，并显着降低了跨上皮电阻。CD 均未改变甘露醇和聚乙二醇 4000 的细胞旁通透性。总之，甲基-β-环糊精的第二代衍生物，特别是 MaRAMEB，可增强紫杉醇在 Caco-2 细胞中的通透性，毒性较小，与 RAMEB 效果相似。
