抗肿瘤药物西美替尼在Caco-2细胞模型中的吸收转运

目的研究抗肿瘤药物西美替尼在Caco-2细胞模型中的吸收转运。方法建立Caco-2细胞转运模型,采用HPLC法测定药物浓度,计算表观渗透系数(P_app),研究西美替尼的Caco-2细胞跨膜转运情况。结果西美替尼在转运过程中没有明显的浓度依赖性。在低浓度范围内,药物的转运速率随着浓度的增加而增加;在较高浓度时达到饱和。西美替尼不同浓度的P_app值(3.91×10^-5、3.29×10^-5、1.90×10^-5和0.95×10^-5cm·s^-1)基本都大于难吸收药物的临界值(1×10^-5cm·s^-1)。西美替尼在Caco-2细胞中的转运呈现较强的方向性,从肠腔面到基底面的P_app值显著大于从基底面到肠腔面的P_app值（2.36～7.58倍）。ATP抑制剂叠氮化钠能显著降低西美替尼的正向转运程度,并升高其反向转运程度。当加入葡萄糖后,从肠腔面到基底面的跨膜转运程度显著降低。结论西美替尼主要是以转运载体介导的主动转运方式被吸收,其小肠吸收情况较好。

Absorption and transportation of anti-cancer drug cimetinib across Caco-2 monolayer model

AIM To study the absorption and transportauon of anti-cancer drug cimetinib using Caco-2 monolayer model.METHODS A highly sensitive HPLC analytic method for cimetinib determination was developed,and the specificity and precision were evaluated.The Caco-2 cell model was established and used to study the transportation of cimetinib. The concentration of cimetinib in transportation medium was measured by HPLC,and the apparent permeability coefficients (P_app)were calculated.RESULTS The developed HPLC analytic method had good specificity and precision. There was no significant concentration dependence in the transportation process of cimetinib.The transportation rate increased with the concentration of cimetinib at the low concentration,and the transportation reached to saturation at the high concentration.The P_appvalues of various concentration of cimetinib(3.91×10^-5,3.29×10^-5,1.90×10^-5and 0.95×10^-5cm·s^-1)almost were higher than the critical P_appvalue of poor absorption drugs(1×10^-5cm·s^-1).The transportation of cimetinib across Caco-2 cell monolayers was highly directional.The P_appvalues of cimetinib from apical side to basolateral side（AP→BL）was significantly higher than those of basolateral side to apical side（BL→AP）with the ratio range from 2.36 to 7.58.Sodium azide,an ATP inhibitor,remarkably decreased transportation of cimetinib from AP→BL direction,and increased the transportation from BL→AP,which suggested that the transportation of cimetinib was energy-dependent.The P_appvalues of cimetinib from AP→BL direction was significantly decreased in the pres- ence of glucose.CONCLUSION The results suggest that cimetinib is mainly actively absorbed by a transporter-mediated process.Cimetinib shows good intestinal absorption,and could be formulated in oral administration dosages.