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首页> 外文期刊>Journal of applied toxicology >Mrp2 is involved in the efflux and disposition of fosinopril
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Mrp2 is involved in the efflux and disposition of fosinopril

机译：Mrp2参与福辛普利的外排和处置

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摘要

The multidrug-resistance-associated proteins 1 and 2 (MRP1/MRP2) are transporters responsible for the efflux of drugs and endogenous compounds. Madin Darby canine kidney (MDCK) cells transfected with the human MRP1 or MRP2 genes were used to assess whether several widely used pharmaceuticals are potential substrates by examining their differential toxicity, accumulation and efflux. Loratadine, an antihistamine, was 1.4-fold less toxic to MRP1 cells and its retention was 1.3-fold lower than that from MDCK control cells. Fosinopril, an angiotensin converting enzyme inhibitor, was 2.4-fold less toxic and its retention was 4.5-fold lower in MRP2-transfected cells compared with control cells. To determine whether fosinopril contributed to a drug-drug interaction, fosinopril efflux was examined in vitro in combination with other known or suspected MRP2 substrates over a period of 20min. When fosinopril was coincubated with desloratadine, loratadine or methotrexate, its retention was increased by 2-, 4.7- and 2-fold, respectively, which likely indicates that a drug-drug interaction is occurring. In vivo studies were conducted, in which FVB wild-type and FVB/Mrp2-/- mice were dosed with fosinopril and the known MRP2 substrate methotrexate, and tissues collected after 1h. In mice lacking Mrp2, drug levels were reduced in the intestine by 1.5-fold, but increased in the liver, serum and kidneys, by 2.1-, 2.9- and 3-fold, respectively. These data suggest that, in the absence of Mrp2, fosinopril alters the retention of a second drug. These findings will help increase our understanding of the role that MRP2 plays in altering the retention and disposition of coadministered pharmaceuticals.
机译：与多药耐药相关的蛋白1和2（MRP1 / MRP2）是负责药物和内源性化合物外排的转运蛋白。通过检查人的MRP1或MRP2基因转染的Madin Darby犬肾（MDCK）细胞，通过检查其差异毒性，累积和外排作用，来评估几种广泛使用的药物是否是潜在的底物。氯雷他定是一种抗组胺药，对MRP1细胞的毒性低1.4倍，其保留率比MDCK对照细胞低1.3倍。与对照细胞相比，在血管紧张素转化酶抑制剂福辛普利中，毒性降低了2.4倍，在MRP2转染的细胞中其保留降低了4.5倍。为了确定福辛普利是否促成药物-药物相互作用，在20分钟内与其他已知或怀疑的MRP2底物一起体外检查了福辛普利外排。福辛普利与去氯雷他定，氯雷他定或甲氨蝶呤共孵育时，其保留率分别提高了2倍，4.7倍和2倍，这可能表明正在发生药物相互作用。进行了体内研究，其中向福斯普利野生型和FVB / Mrp2-/-小鼠施用福辛普利和已知的MRP2底物甲氨蝶呤，并于1h后收集组织。在缺少Mrp2的小鼠中，肠道中的药物水平降低了1.5倍，但在肝脏，血清和肾脏中分别升高了2.1倍，2.9倍和3倍。这些数据表明，在没有Mrp2的情况下，福辛普利会改变第二种药物的保留时间。这些发现将有助于增进我们对MRP2在改变共同给药药物的保留和处置中的作用的了解。

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