Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan.
Drug Chem Toxicol. 2009;32(4):332-7. doi: 10.1080/01480540903130658.
The aim of this study was to examine the effects of 16 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) on P-glycoprotein/MDR1 in Caco-2 cells as an intestinal epithelial cell model. Cells were treated with NSAIDs for 24 hours, and then, the expression of MDR1 mRNA was evaluated by reverse-transcriptase polymerase chain reaction. The function of MDR1 in cells pretreated with NSAIDs for 48 hours was evaluated by measuring the cellular amount of rhodamine123, which is a substrate of MDR1. The expression of MDR1 mRNA was increased by diclofenac, fenbufen, indomethacin, and nimesulide and the tended to be increased by meloxicam, mepirizole, and sulindac. However, pretreatment for 48 hours with diclofenac, indomethacin, or nimesulide, but not fenbufen, resulted in a significant increase in the amount of rhodamine123 accumulated. Although NSAIDs without effects on the expression of MDR1 mRNA altered the accumulation of rhodamine123 significantly, the efflux of rhodamine123 from cells was unchanged. In conclusion, the expression of MDR1 mRNA in Caco-2 cells was demonstrated to be increased by treatment with some NSAIDs, although the transport function of MDR1 was unchanged. These findings imply that the NSAIDs did not cause the drug interaction via MDR1 induction.
本研究旨在考察 16 种非甾体抗炎药（NSAIDs）对 Caco-2 细胞（一种肠上皮细胞模型）P-糖蛋白/MDR1 的影响。细胞用 NSAIDs 处理 24 小时后，通过逆转录聚合酶链反应评估 MDR1 mRNA 的表达。用 NSAIDs 预处理 48 小时后，通过测量 MDR1 的底物罗丹明 123 的细胞内含量来评估 MDR1 的功能。双氯芬酸、布洛芬、吲哚美辛和尼美舒利可增加 MDR1 mRNA 的表达，美洛昔康、甲灭酸和舒林酸也有增加 MDR1 mRNA 表达的趋势。然而，双氯芬酸、吲哚美辛或尼美舒利预处理 48 小时可显著增加罗丹明 123 的积累量，但布洛芬无此作用。尽管对 MDR1 mRNA 表达无影响的 NSAIDs 可显著改变罗丹明 123 的积累，但罗丹明 123 从细胞内的外排并未改变。总之，一些 NSAIDs 可增加 Caco-2 细胞 MDR1 mRNA 的表达，尽管 MDR1 的转运功能未改变。这些发现表明，这些 NSAIDs 并未通过诱导 MDR1 而引起药物相互作用。
