title: Intestinal transport of bis(12)-hupyridone in Caco-2 cells and its improved permeability by the surfactant Brij-35.
abstract: The objective of the present study was to elucidate the mechanisms of intestinal transport of bis(12)-hupyridone (B12H) to predict its oral bioavailability. The effect of the B12H concentration and the contribution of the drug efflux transporters, P-glycoprotein (P-gp or ABCB1) and multidrug resistance-associated proteins (MRPs or ABCC) on B12H absorption were measured and evaluated using the human intestinal epithelial Caco-2 cell monolayer in the presence of transporter inhibitors. The results indicated that B12H was absorbed in a dose-dependent manner at concentrations ranging from 132 to 264 µM. However, only apical efflux was observed in the directional transport studies for B12H below 88 µM (P(app) (AP-to-BL): virtually zero; P(app) (BL-to-AP): 1.591 ± 0.071 × 10(-5)  cm s(-1) ). P-gp and mixed P-gp/MRP inhibitors significantly increased the absorptive transport (P(app) (AP-to-BL)) to 0.619 ± 0.018 × 10(-5) and 0.608 ± 0.025 × 10(-5)  cm s(-1) , respectively, while decreasing secretory transport (P(app) (BL-to-AP)) by >75%. A multiple-MRP inhibitor, probenecid, increased the P(app) (AP-to-BL) to 0.329 ± 0.015 × 10(-5)  cm s(-1) while decreasing the P(app) (BL-to-AP) by 50%. Another multiple-MRP inhibitor, indomethacin, only modestly decreased the P(app) (BL-to-AP) by ∼30% and had no effect on the absorptive transport (P(app) (AP-to-BL): virtually zero). In addition, the effect of various pharmaceutical excipients (e.g. Pluronic F-68, Tween-80 and Brij-35) on B12H transport was determined and compared. Among them, Brij-35 effectively enhanced B12H absorption at a concentration lower than its critical micelle concentration (CMC, 60 µM). Therefore, Brij-35 can be used as a potential enhancer to improve intestinal absorption of B12H for oral administration.
authors.affiliation: Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Yue Qing
authors.initials: YQ
authors.lastname: Hu
authors.forename: Fanny C F
authors.initials: FC
authors.lastname: Ip
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
authors.forename: Yi Fan
authors.initials: YF
authors.lastname: Han
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Ip
mesh_terms: D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism*; D013501:Surface-Active Agents / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015363:Quinolones; D013501:Surface-Active Agents; C528260:bis(12)-hupyridone; D011092:Polyethylene Glycols; C515901:Brij 35