title: Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes.
abstract: 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.
authors: Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, The People's Republic of China.
authors: Wen-Ting
authors: WT
authors: Rong
authors: Ya-Peng
authors: YP
authors: Lu
authors: Qing
authors: Q
authors: Tao
authors: Miao
authors: M
authors: Guo
authors: Yu
authors: Y
authors: Lu
authors: Yong
authors: Y
authors: Ren
authors: Shu-Qin
authors: SQ
authors: Yu
mesh_terms: D000465:Algorithms; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002784:Cholesterol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000077553:Edaravone; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism*; D005079:Excipients; D006801:Humans; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D021962:Membrane Microdomains / Q000378:metabolism; D010477:Perfusion; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D047392:beta-Cyclodextrins; C000592645:hydroxypropyl-sulfobutyl-beta-cyclodextrin; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D000077553:Edaravone; D000983:Antipyrine
keywords: Caco-2 cells; P-glycoprotein; bioavailability; cyclodextrins; edaravone; lipid raft; permeability; pharamcokinetics; solubility