Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression
Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression
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DOI：
10.1172/jci119439
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发表时间：
1997-05-15
影响因子：
15.9
通讯作者：
Watkins, PB
中科院分区：
文献类型：
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作者：
Lown, KS;Bailey, DG;Watkins, PB
非洛地平和其他常用药物与西柚汁一起服用时，口服利用度的增加被认为是由于抑制了细胞色素P450，一种存在于肝脏和肠道中的细胞色素P450。为了评价反复摄入西柚汁对CYP3A4表达的影响，10名健康男性每天3次服用8盎司西柚汁，连续6d。在服用西柚汁前后，取小肠和结肠粘膜活检，测定口服非洛地平动力学，并用[C-14 N-甲基]红霉素呼气试验测定肝脏CYP3A4活性。西柚汁不改变肝脏细胞色素P3A4活性、结肠细胞色素P3A5水平，或小肠P-糖蛋白、绒毛蛋白、细胞色素P1A1和细胞色素P2D6浓度。而小肠上皮(肠细胞)中细胞色素P3A4的浓度下降了62%(P=0.0006)，而细胞色素P3A4mRNA的表达水平没有相应的变化。此外，在饮用西柚汁前测得的肠细胞色素P3A4浓度与服用第1杯或第16杯西柚汁时C-max的增加呈正相关(分别为r=0.67P=0.043和r=0.71P=0.022)。我们认为，西柚汁对非洛地平口服动力学的影响机制之一是选择性地下调小肠中的细胞色素P3A4。
The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [C-14 N-methyl] erythromycin breath test in each subject.Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in C-max when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0.67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.