Strauch Katja, Lutz Ursula, Bittner Nataly, Lutz Werner K
Department of Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.
Food Chem Toxicol. 2009 Aug;47(8):1928-35. doi: 10.1016/j.fct.2009.05.004. Epub 2009 May 13.
Grapefruit juice (GFJ) has been shown to affect the pharmacokinetics of a large number of drugs, essentially by inhibition of efflux transporters and CYP3A4 monooxygenase in the small intestine. The GFJ dose usually used in human studies was one glass single-strength (1x). Information on a respective dose-response relationship is not available. We investigated the effect of GFJ of different concentration (0.25 x, 0.5x, 1x, 2x) dosed in biweekly intervals in 19 volunteers. Components considered responsible for drug interactions, naringin, naringenin, bergamottin, and 6',7'-dihydroxybergamottin were determined by LC-tandem mass spectrometry. Immediately after ingestion of GFJ, participants took an aqueous solution of dextromethorphan (DEX) as probe drug. Urine was collected in two sampling periods, 0-2 and 2-4h, and excreted amounts of DEX and five metabolites associated with CYP3A4 and/or CYP2D6 enzyme activity were determined. Effects of GFJ were analyzed by the Wilcoxon matched-pairs signed-rank test against an average of four water control experiments. Two effects were highly significant: (i) a delay of total metabolite excretion in the first 2h and (ii) an inhibition of the CYP3A4-dependent metabolic pathways. Effect magnitude and significance levels were dose-dependent and indicated 200 ml 1x GFJ as "lowest observed effect level" LOEL.
葡萄柚汁（GFJ）已被证明会影响大量药物的药代动力学，主要是通过抑制小肠中的外排转运蛋白和CYP3A4单加氧酶。人体研究中通常使用的GFJ剂量是一杯单浓度（1倍）。目前尚无关于相应剂量反应关系的信息。我们调查了19名志愿者每两周服用一次不同浓度（0.25倍、0.5倍、1倍、2倍）GFJ的效果。通过液相色谱-串联质谱法测定了被认为是药物相互作用原因的成分，柚皮苷、柚皮素、佛手柑内酯和6'，7'-二羟基佛手柑内酯。在摄入GFJ后，参与者立即服用右美沙芬（DEX）水溶液作为受试药物。在0-2小时和2-4小时两个采样期收集尿液，并测定DEX及其与CYP3A4和/或CYP2D6酶活性相关的五种代谢物的排泄量。通过Wilcoxon配对符号秩检验，对照四个水对照实验的平均值，分析GFJ的效果。有两个影响非常显著：（i）前2小时总代谢物排泄延迟；（ii）CYP3A4依赖性代谢途径受到抑制。效应大小和显著性水平呈剂量依赖性，表明200毫升1倍GFJ为“最低观察到效应水平”（LOEL）。
