Absorption and transportation of anti-cancer drug cimetinib across Caco-2 monolayer model
ZHANG Jianming~(1,2),REN Xiaoqing~1,SHA Xianyi~1,FANG Xiaoling~1(1 Department of Pharmaceutics,School of Pharmacy, Fudan University,Shanghai 201203,China;2 Shanghai Mental Health Center,School of Medicine,Shanghai Jiaotong University,Shanghai 201108,China)
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_(app)values of various concentration of cimetinib(3.91×10~(-5),3.29×10~(-5),1.90×10~(-5)and 0.95×10~(-5)cm·s~(-1))almost were higher than the critical P_(app)value of poor absorption drugs(1×10~(-5)cm·s~(-1)).The transportation of cimetinib across Caco-2 cell monolayers was highly directional.The P_(app)values 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_(app)values 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.