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首页> 外文期刊>Life sciences >Non-steroidal anti-inflammatory drugs affect the methotrexate transport in IEC-6 cells.
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Non-steroidal anti-inflammatory drugs affect the methotrexate transport in IEC-6 cells.

机译：非甾体类抗炎药会影响甲氨蝶呤在IEC-6细胞中的转运。

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摘要

Methotrexate (MTX) is used not only for the cancer chemotherapy but also for the treatment of rheumatic disease, often together with non-steroidal anti-inflammatory drugs (NSAIDs). MTX is actively cotransported with H(+) in the small intestine, mediated by a reduced folate carrier (RFC). The coadministration of some NSAIDs with MTX to rats caused a decrease of MTX absorption through the small intestine. This may be due to the uncoupling effect of oxidative phosphorylation of the NSAIDs. The present study investigated whether flufenamic acid, diclofenac and indomethacin, NSAIDs, decreased ATP content of rat-derived intestinal epithelial cell line IEC-6 cells and affected the MTX transport in IEC-6 cells. The MTX uptake in IEC-6 cells was dependent on medium pH and maximum around pH 4.5-5.5. The MTX uptake was composed of a transport inhibited by 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS) and a non-saturable one. The DIDS-sensitive component in the MTX uptake showed a saturation kinetics (Michaelis-Menten constant (Km): 3.91 +/- 0.52 microM, Maximum velocity (Vmax): 94.66 +/- 6.56 pmol/mg protein/5 min). The cellular ATP content in IEC-6 cells decreased significantly at 30 min after the cells were started to incubate with the NSAIDs (250 microM flufenamic acid, 500 microM diclofenac and 500 microM indomethacin). The MTX uptake in IEC-6 cells in the presence of the NSAIDs decreased with the reduction of cellular ATP content and showed a good correlation with the ATP content (correlation coefficient: 0.982). Thus it seems likely that the ATP content in IEC-6 cells with the NSAIDs decreased due to the uncoupling effect of oxidative phosphorylation of the NSAIDs, resulting in the inhibition of the secondary active transport of MTX in IEC-6 cells. The present results also suggest that IEC-6 cells are useful to evaluate the drug interaction relating to this carrier system.
机译：甲氨蝶呤（MTX）通常与非甾体抗炎药（NSAID）一起用于癌症化学疗法，也用于风湿性疾病的治疗。在减少的叶酸载体（RFC）的介导下，MTX在小肠中与H（+）积极共转运。某些NSAIDs与MTX共同给药于大鼠会导致MTX通过小肠吸收减少。这可能是由于NSAID的氧化磷酸化产生的解偶联作用。本研究调查了氟芬那酸，双氯芬酸和消炎痛，NSAIDs是否降低了大鼠肠上皮细胞系IEC-6细胞的ATP含量并影响了IEC-6细胞中的MTX转运。 IEC-6细胞中MTX的吸收取决于中等pH值，最大pH值约为4.5-5.5。 MTX的吸收是由被4、4'-二异硫氰基茂铁2、2'-二磺酸（DIDS）和一种不饱和的抑制的转运组成的。在MTX摄取中对DIDS敏感的组分显示出饱和动力学（Michaelis-Menten常数（Km）：3.91 +/- 0.52 microM，最大速度（Vmax）：94.66 +/- 6.56 pmol / mg蛋白质/ 5分钟）。在开始与NSAIDs（250 microM氟芬那酸，500 microM双氯芬酸和500 microM吲哚美辛）孵育30分钟后，IEC-6细胞中的细胞ATP含量显着降低。在存在NSAID的情况下，IEC-6细胞中MTX的摄取随细胞ATP含量的降低而降低，并显示出与ATP含量的良好相关性（相关系数：0.982）。因此，由于NSAID的氧化磷酸化的解偶联作用，IEC-6细胞中具有NSAID的ATP含量降低的可能性似乎降低了，从而抑制了IEC-6细胞中MTX的二次活性转运。目前的结果还表明，IEC-6细胞可用于评估与此载体系统有关的药物相互作用。

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