Glaeser H, Bailey D G, Dresser G K, Gregor J C, Schwarz U I, McGrath J S, Jolicoeur E, Lee W, Leake B F, Tirona R G, Kim R B
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Clin Pharmacol Ther. 2007 Mar;81(3):362-70. doi: 10.1038/sj.clpt.6100056. Epub 2007 Jan 10.
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 1B3, 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. OATP1A2 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 OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 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.
本研究的目的是评估人类肠道药物转运体的表达程度，确定药物摄取转运体OATP1A2的亚细胞定位，然后评估饮用葡萄柚汁对OATP1A2表达相对于细胞色素P450 3A4和MDR1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体的表达。在转染了转运体的细胞系中测量不同转运体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。使用实时聚合酶链反应和蛋白质印迹分析确定葡萄柚汁对肠道转运体表达的影响。在健康志愿者的十二指肠中，表达了一系列CYP酶以及摄取和外排转运体。重要的是，被认为是肝脏特异性的摄取转运体，如OATP1B1和1B3，以及OATP2B1和1A2在肠道中也有表达。然而，在OATP转运体中，在体外评估时只有OATP1A2能够摄取非索非那定。OATP1A2与MDR1共定位于肠细胞的刷状缘结构域。在服用非索非那定的同时或之前2小时饮用葡萄柚汁与口服非索非那定的血浆暴露量降低有关，而OATP1A2或MDR1的肠道表达未受影响。总之，人类肠道中表达了一系列药物摄取和外排转运体。OATP1A2可能是负责非索非那定吸收的关键肠道摄取转运体，其受到抑制会导致葡萄柚汁效应。虽然短期饮用葡萄柚汁与非索非那定的可用性降低有关，但OATP1A2或MDR1的表达未受影响。
