流出
碳酸钙-2
紫杉醇
P-糖蛋白
化学
并行传输
维拉帕米
药代动力学
顶膜
被动运输
作用机理
生物利用度
上皮
药理学
上皮极性
磁导率
体外
生物
生物化学
细胞
内科学
膜
化疗
医学
多重耐药
钙
抗生素
遗传学
有机化学
作者
U K Walle,Thomas Walle
摘要
Taxol (paclitaxel) belongs to a new class of antimicrotubule anticancer drugs with clinical activity against common solid tumors and acute leukemias. Preclinical studies have suggested that taxol is not absorbed after oral doses. However, whether the observed low oral bioavailability is the result of poor absorption or extensive presystemic hepatic metabolism is not clear. For this reason, we studied the transepithelial flux of taxol, using the human colonic cell line Caco-2 as a model. The cells were grown to confluency on permeable polycarbonate membrane inserts, to permit flux experiments after loading of [3H]taxol on either the apical or basolateral side. The flux of taxol across the Caco-2 cell layer was linear with time for up to 3 hr. The flux from the basolateral to the apical side was 4-10 times greater than that from the apical to the basolateral side. Whereas the absorptive transport appeared linearly related to the taxol concentration (0.5-20 microM), the efflux was saturable. The apparent KM of the active efflux component was 16.5 microM. Verapamil (50 microM) significantly decreased the active transport component. These data support the conclusion that rapid passive diffusion of taxol through the intestinal epithelium is partially counteracted by the action of an outwardly directed efflux pump, presumably P-glycoprotein. However, the relatively high apparent permeability coefficient for the apical to basolateral taxol transport (4.4 +/- 0.4 x 10(-6) cm/s; N = 17) suggests that the drug may still be effectively absorbed in the intestinal tract.
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