Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, The People's Republic of China.
J Pharm Sci. 2014 Feb;103(2):730-42. doi: 10.1002/jps.23807. Epub 2013 Dec 5.
The objective of the study was to evaluate the effect of hydroxypropyl-sulfobutyl-β-cyclodextrin (HP-SBE-βCD) on the bioavailability and intestinal absorption of edaravone, and identify its mechanism of action. We devised HP-SBE-βCD as a carrier and modulator of P-glycoprotein (Pgp) efflux pump, and edaravone as a model drug, and prepared edaravone/HP-SBE-βCD inclusion complex. HP-SBE-βCD improved the water solubility and enhanced the bioavailability of edaravone by 10.3-fold in rats. Then, in situ single-pass intestinal perfusion showed that HP-SBE-βCD had an effect of improving the permeability and inhibiting the efflux of edaravone. Furthermore, the effects of HP-SBE-βCD on Pgp were achieved through interfering with the lipid raft and depleting the cholesterol of enterocytes membrane. From the results, we presented the novel mechanisms. First, edaravone/HP-SBE-βCD had a lower release from the inclusion compound to protect edaravone from the low pH of the stomach. Then, HP-SBE-βCD modulated the membrane microenvironment of intestinal absorption epithelial cells. At last, the result was that HP-SBE-βCD enhanced the absorption of edaravone by interfering with Pgp. In conclusion, HP-SBE-βCD improves the bioavailability of drug not only because of its enhancing water solubility of the drug, but also because it modulates the Pgp-mediated efflux from enterocytes.
本研究旨在评估羟丙基磺丁基-β-环糊精（HP-SBE-βCD）对依达拉奉生物利用度和肠道吸收的影响，并探讨其作用机制。我们将 HP-SBE-βCD 设计为 P 糖蛋白（Pgp）外排泵的载体和调节剂，将依达拉奉设计为模型药物，并制备了依达拉奉/HP-SBE-βCD 包合物。HP-SBE-βCD 提高了依达拉奉的水溶性，使大鼠体内的生物利用度提高了 10.3 倍。然后，在体单向肠灌流实验表明，HP-SBE-βCD 可改善依达拉奉的通透性并抑制其外排。此外，HP-SBE-βCD 通过干扰质膜筏和耗竭肠上皮细胞的胆固醇来影响 Pgp。由此，我们提出了新的作用机制。首先，依达拉奉/HP-SBE-βCD 从包合物中缓慢释放，以保护依达拉奉免受胃内低 pH 的影响。然后，HP-SBE-βCD 调节肠吸收上皮细胞的膜微环境。结果是 HP-SBE-βCD 通过干扰 Pgp 增强了依达拉奉的吸收。总之，HP-SBE-βCD 提高药物的生物利用度不仅是因为其增强了药物的水溶性，还因为它调节了 Pgp 介导的肠细胞外排。
