目的 研究花椒毒酚(1)、花椒毒素(2)、欧前胡素(3)、异欧前胡素(4)、8-甲氧基异欧前胡素(蛇床灵,5)和异茴芹素(6)6个线型呋喃香豆素类化合物在人源肠Caco-2细胞单层模型的吸收特性. 方法 应用人源结肠腺癌细胞系Caco-2细胞单层模型测试6个香豆素类化合物从绒毛面(AP端)到基底面(BL端)、BL端到AP端2个方向的转运过程.应用偶联紫外检测器的高效液相色谱法对上述6个香豆素进行定量分析,计算转运参数和表观渗透系数(P_app),并与阳性对照药普萘洛尔和阿替洛尔进行比较.根据1～6、补骨脂素(7)、佛手酚(8)、佛手酚葡萄糖苷(9)、佛手内酯(10)、紫花前胡苷(11)、紫花前胡苷元(12)、前胡苷V(13)、伞形花内酯(14)、甲氧基欧芹素(15)、当归醇-A(16)、当归醇-B(17)在Caco-2细胞单层模型的吸收特性,总结这些香豆素类化合物结构、亲脂性与吸收的规律. 结果 6个香豆素类化合物双向转运的P_app值皆在10^-5 cm/s数量级,与在Caco-2细胞单层模型上呈良好吸收的普萘洛尔的P_app值在同一数量级,且皆通过被动吸收机制通过Caco-2细胞单层. 结论 6个香豆素皆属于吸收良好的化合物.香豆素1～17的lg P_{app AP→BL}与lg D(pH 7.35)呈显著S型相关,主要通过被动扩散机制吸收转运.

Objective To study the absorption and transportation characteristic of xanthotoxol (1), xanthotoxin (2), imperatorin (3), isoimperatorin (4), cnidilin (5), and isopimpinellin (6), which were classified as the linear type furocoumarins, in a model of Caco-2 cell monolayers in human intestinal epithelium. Methods Caco-2 (the human colon adenocarcinoma cell lines) cell monolayer was used as an intestinal epithelial cell model. The permeability of the six coumarins from apical side (AP side) to basolateral side (BL side) or from BL side to AP side was evaluated. The concentration of the six coumarins was measured by HPLC coupled with UV detector. Transportation parameters and permeability coefficients (P_app) were then calculated, and P_app values were compared with the reported values for model compounds, Propranolol and Atenolol. Based on the absorption and transportation characteristic of coumarins 1-6, and psoralen (7). bergaptol (8). bergaptol-O-β-D-glucopyranoside (9). bergapten (10). nodakenin (11). nodakenetin (12). decuroside V (13). umbelliferone (14), osthole (15). angelol-A (16). and angelol-B (17) in a model of Caco-2 cell monolayer, the relationship of absorption and transportation with diversed chemical structures and lipophilicity was reviewed. Results In the Caco-2 cell monolayer model, the P_{app magnitudes of the linear furocoumarins 1-6 were 10?5 cm/s in the bi-directional transport, which was identical with Propranolol. And the permeability of Caco-2 cell monolayer is mainly via passive absorption. Conclusion The above-mentioned linear furocoumarins 1-6 are well-absorbed compounds. The results show that a significant Sigmoid dependence of permeability on lg Papp AP→BL and lg D at pH 7.35 of all 1-17 furocoumarins can be absorbed across intestinal epithelial cells by passive diffusion mechanism.}

科技部“863”资助项目(2002AA2Z343C,2004AA2Z3783);北京市科委资助项目(Z0004105040311);国家自然科学基金(30672609);“十一五”国家科技支撑计划(2006BAI06A01-02);天然药物及仿生药物国家重点实验室开放课题资助项目