Bailey D G, Kreeft J H, Munoz C, Freeman D J, Bend J R
Department of Medicine, London Health Sciences Centre, Ontario, Canada.
Clin Pharmacol Ther. 1998 Sep;64(3):248-56. doi: 10.1016/S0009-9236(98)90173-4.
To test whether naringin or 6',7'-dihydroxybergamottin is a major active substance in grapefruit juice-felodipine interaction in humans.
Grapefruit juice was separated by means of centrifugation and filtration into supernatant and particulate fractions, which were then assayed for naringin and 6',7'-dihydroxybergamottin. The effect of these fractions, grapefruit juice (containing comparable amounts of both fractions), and water on the pharmacokinetics of oral felodipine were assessed in 12 healthy men in a randomized, 4-way crossover study.
The amounts of naringin and 6',7'-dihydroxybergamottin in the supernatant fraction (148 mg and 1.85 mg) were greater than in the particulate fraction (7 mg and 0.60 mg). The area under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of felodipine were higher with supernatant fraction (81 nmol.h/L and 20 nmol/L), particulate fraction (117 nmol.h/L and 24 nmol/L), and grapefruit juice (130 nmol.h/L and 33 nmol/L) compared with water (53 nmol.h/L and 11 nmol/L). However, the supernatant fraction had a lower AUC for felodipine and a similar Cmax of felodipine relative to the particulate fraction. The supernatant fraction neither augmented the AUC of the primary metabolite dehydrofelodipine nor decreased the AUC ratio of dehydrofelodipine to felodipine compared with water. Individually the supernatant fraction consistently produced lower felodipine AUC and Cmax compared with grapefruit juice. In contrast, the particulate fraction had values ranging from more than grapefruit juice to less than supernatant fraction.
Naringin and 6',7'-dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice-felodipine interaction. The variable effect with the particulate fraction may result from erratic bioavailability of unidentified primary active substances. The findings show the importance of in vivo testing to determine the ingredients in grapefruit juice responsible for inhibition of cytochrome P450 3A4 in humans.
检测柚皮苷或6'，7'-二羟基香柠檬苦素是否为葡萄柚汁与非洛地平在人体内相互作用的主要活性物质。
通过离心和过滤将葡萄柚汁分离为上清液和颗粒部分，然后对其进行柚皮苷和6'，7'-二羟基香柠檬苦素的测定。在一项随机、四路交叉研究中，对12名健康男性评估了这些部分、葡萄柚汁（含有等量的这两个部分）和水对口服非洛地平药代动力学的影响。
上清液部分中柚皮苷和6'，7'-二羟基香柠檬苦素的含量（分别为148毫克和1.85毫克）高于颗粒部分（分别为7毫克和0.60毫克）。与水（分别为53纳摩尔·小时/升和11纳摩尔/升）相比，非洛地平的血浆浓度-时间曲线下面积（AUC）和峰浓度（Cmax）在上清液部分（分别为81纳摩尔·小时/升和20纳摩尔/升）明显升高，颗粒部分（分别为117纳摩尔·小时/升和24纳摩尔/升）和葡萄柚汁（分别为130纳摩尔·小时/升和33纳摩尔/升）也明显升高。然而，相对于颗粒部分，上清液部分的非洛地平AUC较低，而Cmax相似。与水相比，上清液部分既未增加主要代谢物脱氢非洛地平的AUC，也未降低脱氢非洛地平与非洛地平的AUC比值。单独来看，上清液部分的非洛地平AUC和Cmax始终低于葡萄柚汁。相比之下，颗粒部分的值从高于葡萄柚汁到低于上清液部分不等。
柚皮苷和6'，7'-二羟基香柠檬苦素不是主要活性成分，尽管它们可能对葡萄柚汁与非洛地平的相互作用有一定作用。颗粒部分的可变效应可能是由于未鉴定的主要活性物质的生物利用度不稳定所致。研究结果表明了体内试验对于确定葡萄柚汁中抑制人体细胞色素P450 3A4的成分的重要性。
