Taxol transport by human intestinal epithelial Caco-2 cells.
Taxol transport by human intestinal epithelial Caco-2 cells.
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发表时间：
1998-04
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通讯作者：
U. Walle;Thomas Walle
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作者：
U. Walle;Thomas Walle
紫杉醇(紫杉醇)是一类新型的抗微管抗癌药物，具有抗常见实体瘤和急性白血病的临床活性。临床前研究表明，紫杉醇在口服后不会被吸收。然而，观察到的口服生物利用度低是否是吸收不良或广泛的体循环前肝脏代谢的结果尚不清楚。为此，我们以人结肠癌细胞系Caco-2为模型，研究了紫杉醇的跨上皮通量。细胞在可渗透的聚碳酸酯薄膜插入物上生长至融合，以允许在顶端或基底侧面负载[~3H]紫杉醇后的通量实验。紫杉醇通过Caco-2细胞层的通量与时间呈线性关系，最长可达3小时。从基底外侧到根尖侧的流量是从根尖到基底外侧的流量的4~10倍。而吸收转运与紫杉醇浓度(0.5-20微米)呈线性关系，而外排是饱和的。主动外排组分的表观Km为16.5微米。维拉帕米(50微米)显著降低主动转运成分。这些数据支持这样的结论，即紫杉醇通过肠上皮的快速被动扩散部分地被外向泵的作用所抵消，推测是P-糖蛋白。然而，较高的表观渗透系数(4.4+/-0.4×10(-6)cm/S；N=17)提示药物仍可在肠道有效吸收。
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.