Intestinal drug transporter expression and the impact of grapefruit juice in humans
Intestinal drug transporter expression and the impact of grapefruit juice in humans
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DOI：
10.1038/sj.clpt.6100056
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发表时间：
2007-03-01
影响因子：
6.7
通讯作者：
Kim, R. B.
中科院分区：
文献类型：
--
作者：
Glaeser, H.;Bailey, D. G.;Kim, R. B.
本研究的目的是评估人肠道药物转运蛋白表达的程度，确定药物摄取转运蛋白OATP 1A2的亚细胞定位，然后评估葡萄柚汁摄入对OATP 1A2表达（相对于细胞色素P450 3A4和MDR 1）的影响。使用人十二指肠活检样本评估药物摄取和外排转运蛋白的表达。在转运蛋白转染的细胞系中测量不同转运蛋白对非索非那定的摄取。我们研究了葡萄柚汁对口服非索非那定药代动力学的影响。采用实时荧光定量聚合酶链反应和Western印迹法检测葡萄柚汁对肠道转运蛋白表达的影响。在健康志愿者的十二指肠中，表达了一系列的胰蛋白酶以及摄取和外排转运蛋白。重要的是，被认为是肝脏特异性的摄取转运蛋白，如OATP 1B1和1133，以及OATP 2B1和1A2在肠道中表达。然而，在体外评估时，在OATP转运蛋白中，仅OATP 1A2能够摄取非索非那定。0ATP 1A2与MDR 1共定位于肠上皮细胞刷状缘结构域。同时或在非索非那定给药前2小时饮用葡萄柚汁与口服非索非那定血浆暴露量降低相关，而肠内0ATP 1A2或MDR 1的表达不受影响。总之，一系列药物摄取和外排转运蛋白在人肠道中表达。0ATP 1A2可能是非索非那定吸收的关键肠道摄取转运蛋白，其抑制导致葡萄柚汁效应。尽管短期摄入葡萄柚汁与非索非那定的可用性降低相关，但OATP1A2或MDR 1表达不受影响。
The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1133, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. 0ATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either 0ATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. 0ATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.