Article

Absorption and transportation characteristic of six linear furocoumarins in a model of Caco-2 cell monolayer in human intestine

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Abstract

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 (Papp) 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 Papp 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 1g Papp AP→BL and 1g D at pH 7.35 of all 1-17 furocoumarins can be absorbed across intestinal epithelial cells by passive diffusion mechanism.

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... The above studies suggest that coumarins are the prime ingredients contributing to the CNS activity of APR. The intestinal absorptions of main coumarins from APR, such as umbelliferone, osthol, columbianadin, columbianetin acetate, psoralen, bergapten, xanthotoxin and isoimperatorin, have been studied with human colon adenocarcinoma cell line (Caco-2) cell monolayer in our group, and all of them are defined as well or moderately intestinal absorbed compounds [18][19][20]. Therefore, it is necessary to study the penetration abilities of the main coumarins of APR through the blood-brain barrier (BBB) for accessing its CNS pharmacological activities. ...
... In this study, it was notable that the coumarin penetrations across MDCK-pHaMDR cell monolayer were not well correlated with their log P. Theoretical passive drug absorption [28] and experimental transport across intestinal epithelial cells [29] have proved that lipophilicity has a close relationship with the tansepithelial permeability of compounds. Our previous works have demonstrated the sigmoid relationship between permeability log (Papp AP-BL*MW 0.5 ) and log D of neolignans [30] and coumarins [20] in Caco-2 cell monolayer. In this study, log D (at pH 7.4) was chosen as the index of lipophilicity, calculated with Pallas 3.3.2.6 ADME/Tox Software (CompuDrug, Bal Harbor, FL,USA) ( Table 1) The sigmoid curve suggested that the BBB transepithelial permeabilities of coumarins (compounds 1, 3, 5, 6, 7, 8, 9, 12) with moderate log D (1.0-3.5) were relatively high and less affected by the change of log D, while the penetrations of those with higher log D (3.5-4.5) ...
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