Liang E, Proudfoot J, Yazdanian M
Pharmaceutics Department, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT 06877, USA.
Pharm Res. 2000 Oct;17(10):1168-74. doi: 10.1023/a:1026450326712.
To investigate the mechanisms involved in transport of sulfasalazine in Caco-2 cells.
Permeability coefficients of sulfasalazine and its analogs across Caco-2 cell monolayers were measured as a function of direction of transport, energy and concentration dependence, and in the presence of inhibitors of various cellular efflux pumps and transporters.
Permeability coefficients of sulfasalazine across Caco-2 cell monolayers were approximately 342-, 261-, and 176-fold higher from basolateral to apical direction (BL-->AP) than from apical to basolateral direction (AP-->BL) at 100, 200, and 500 microM, respectively. Carrier permeability coefficient, non-saturable membrane permeability coefficient, and Michaelis constant were estimated to be 1.4x10(-5) cm/s, 1.9x10(-8) cm/s, and 369 microM, respectively. The efflux of sulfasalazine was completely blocked at 4 degrees C and in the presence of an uncoupler of oxidative phosphorylation. Using cellular efflux inhibitors, the permeability of sulfasalazine was shown to depend on multidrug resistance-associated protein and anion sensitive transport mechanisms. Structure-permeability studies showed that the affinity of sulfasalazine for the cellular efflux pumps and transporters in Caco-2 cells depended strongly on the carboxylic acid functional group.
The permeability of sulfasalazine across Caco-2 cell monolayer is very low due to its strong interaction with multiple cellular efflux pumps and transporters. This may partially explain its low absorption in vivo.
研究柳氮磺胺吡啶在Caco-2细胞中的转运机制。
测量柳氮磺胺吡啶及其类似物跨Caco-2细胞单层的渗透系数，作为转运方向、能量和浓度依赖性的函数，并在存在各种细胞外排泵和转运体抑制剂的情况下进行测量。
在100、200和500微摩尔浓度下，柳氮磺胺吡啶跨Caco-2细胞单层从基底外侧到顶端方向（BL→AP）的渗透系数分别比从顶端到基底外侧方向（AP→BL）高约342倍、261倍和176倍。载体渗透系数、非饱和膜渗透系数和米氏常数估计分别为1.4×10⁻⁵厘米/秒、1.9×10⁻⁸厘米/秒和369微摩尔。柳氮磺胺吡啶的外排在4℃和存在氧化磷酸化解偶联剂的情况下完全被阻断。使用细胞外排抑制剂，柳氮磺胺吡啶的渗透性显示取决于多药耐药相关蛋白和阴离子敏感转运机制。结构-渗透性研究表明，柳氮磺胺吡啶对Caco-2细胞中细胞外排泵和转运体的亲和力强烈依赖于羧酸官能团。
柳氮磺胺吡啶跨Caco-2细胞单层的渗透性非常低，这是由于它与多种细胞外排泵和转运体的强烈相互作用。这可能部分解释了其在体内的低吸收。
