Legen Igor, Kristl Albin
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
Eur J Pharm Biopharm. 2003 Jul;56(1):87-94. doi: 10.1016/s0939-6411(03)00039-0.
The aim of this study was to elucidate transport mechanisms of ketoprofen (monocarboxylic acid with pK(a) 4.6) across rat jejunum in vitro using side-by-side diffusion cells. When the tissue was incubated on the mucosal and serosal sides with buffer of pH 7.51 (pH of the mucosal surface was 7.08), ketoprofen permeated faster in the mucosal-to-serosal than in the opposite direction. No asymmetry in transport was observed when 2 mM mucus disrupting agent 1,4-dithio-DL-threitol (pH of the mucosal surface increased to 7.21) was added to the mucosal side. Mucosal-to-serosal permeability of ketoprofen increased three times when the pH of the incubation medium was changed from 8.06 (pH of the mucosal surface was 7.34) to 6.07 (pH of the mucosal surface was 5.95), while no pH dependence was found under ATP-depletion caused by sodium azide. In the ketoprofen concentration range from 0.125 to 5 mM no saturation of transport was observed. Moreover, ketoprofen transport was not changed in the presence of 2 mM benzoate, 10 and 20 mM acetate, 20 mM L-lactate (substrates for monocarboxylate transporter 1, MCT1) and 1 mM alpha-cyano-4-hydroxy-cinnamic acid (an inhibitor of MCT1). These results indicate that ketoprofen is transported across rat jejunum in vitro by pH and energy dependent transport mechanisms, and most probably not by MCT1.
本研究的目的是使用并排扩散池在体外阐明酮洛芬（pK(a) 4.6的一元羧酸）在大鼠空肠中的转运机制。当组织在pH 7.51的缓冲液（粘膜表面pH为7.08）中于粘膜侧和浆膜侧孵育时，酮洛芬从粘膜到浆膜的渗透速度比相反方向更快。当向粘膜侧添加2 mM粘液破坏剂1,4-二硫代-DL-苏糖醇（粘膜表面pH升至7.21）时，未观察到转运的不对称性。当孵育介质的pH从8.06（粘膜表面pH为7.34）变为6.07（粘膜表面pH为5.95）时，酮洛芬的粘膜到浆膜渗透率增加了三倍，而在叠氮化钠引起的ATP耗竭情况下未发现pH依赖性。在0.125至5 mM的酮洛芬浓度范围内，未观察到转运饱和。此外，在存在2 mM苯甲酸盐、10和20 mM乙酸盐、20 mM L-乳酸盐（单羧酸转运体1，MCT1的底物）和1 mM α-氰基-4-羟基肉桂酸（MCT1的抑制剂）的情况下，酮洛芬的转运没有变化。这些结果表明，酮洛芬在体外通过pH和能量依赖性转运机制在大鼠空肠中转运，最有可能不是通过MCT1转运。
