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学科主题: 物理化学
题名: Poor Membrane Permeability Ability of SANT75 across Caco-2 Cell Monolayer Due to high Cellular Accumulation
作者: Li N(李娜) ;  Hu Y(胡莹) ;  Yu Y(于洋) ;  Li S(李松) ;  Che C(车超) ;  Yang L(杨凌)
会议名称: 9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics
会议日期: 2010-9-4
出版日期: 2010-09-04
会议地点: 土耳其
通讯作者: 杨凌
部门归属: 十八室
主办者: 国际药物代谢协会
摘要: ABSTRACT BACKGROUND. SANT75(Smoothened antagonist 75) has been identified and characterized as Smo inhibitor by screening from a small molecule library designed based on the scaffold of Smo agonist SAG[1]. It is a structural analog of SAG with the methyl group substituted by propyl group. As part of effort to address pharmacological effects of SANT75, we investigate the permeability of SANT75 using an in vitro cell culture model, Caco-2 cell monolayer. METHOD. The viability of Caco-2 cells in the presence of SANT75 was measured using Sulforhodamine B(SRB) cytotoxicity experiment. The Caco-2 cells were cultured in Transwell-clear inserts with 1.12cm2 permeable polyester membrane in 12-well plates for 21days. The integrity of the cell monolayers was evaluated by measuring transepithelial electrical resistance(TEER) using a Millicell-ERS voltohmmeter and paracellular leakage of Lucifer Yellow. Furthermore, permeability coefficients(Papp) of dexamethasone and digoxin were measured as additional markers. Transport study was initiated by replacing the transport medium on the apical side with an equal volume of HBSS/HEPES buffer containing 10 μM SANT75 and fresh HBSS/HEPES buffer on the basolateral side. 100 μl of the medium from the receiver compartment was taken at every 30 min up to 2 h, and the sample was quantified by ultra fast liquid chromatograph(UFLC) method. To determine whether cellular accumulation occured in Caco-2 cells or not, the methanol extract of cell collection was analyzed by UFLC method mentioned above. RESULTS. Based on the cytotoxicity assay results, the concentration of 10μM was selected for transport experiment. The Papp(A-B) values of dexamethasone and digoxin were (5.1±0.5)×10-6 cm•s-1 and (2.0±0.04) ×10-6 cm•s-1 respectively, which were in accord with the reported values previously for permeability assay with the same tested compounds[2,3]. No celluar accumulation of dexamethasone and digoxin was found during the transport experiment. However, using SANT75 as tested compound, the amounts permeated to the basolateral side was too low to be detected, while a high cellular accumulation was detected in the cell extracts. The cellular accumulation rate reached to (75.2±0.1)% and the amount of SANT75 retained in the apical side was only (4.7±0.1)%, thus the total recovery percentage during the transport experiment was (79.9±0.1)%. CONCLUSION. SANT75 showed poor permeability ability across Caco-2 cell monolayer due to high cellular accumulation. The phenomenon is very uncommon and might be due to its high cellular protein binding, which is worthy of further research. The results suggested that it was necessary to optimize SANT75 structurally further to gain good membrane permeability keeping its activity. References [1] Yang HB, Xiang J, Wang ND, et al. Converse Conformational Control of Smoothened Activity by Structurally Related Small Molecules[J]. Journal of Biological Chemistry. 2009, 284(31): 20876-20884. [2] Zambito Y, Fogli S , Zaino C, et al. Synthesis, Characterization and Evaluation of Thiolated Quaternary Ammonium-chitosan Conjugates for Enhanced Intestinal Drug Permeation[J]. European Journal of Pharmaceutical Sciences, 2009, 38(2): 112-120. [3] Han Y, Tan TMC, Lim LY. In Vitro and in Vivo Evaluation of the Effects of Piperine on P-gp Function and Expression[J]. Toxicology and Applied Pharmacology, 2008, 230(3): 283-289. Kewords: SANT75,Permeability,Accumulation,Caco-2 cell monolayer
语种: 中文
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内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/114336
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Li N,Hu Y,Yu Y,et al. Poor Membrane Permeability Ability of SANT75 across Caco-2 Cell Monolayer Due to high Cellular Accumulation[C]. 见:9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics. 土耳其. 2010-9-4.
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