Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients
Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients
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DOI：
10.1067/mcp.2000.110774
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发表时间：
2000-11-01
影响因子：
6.7
通讯作者：
Bend, JR
中科院分区：
文献类型：
--
作者：
Bailey, DG;Dresser, GR;Bend, JR
目的：为了确定未加工的葡萄柚是否会引起药物相互作用，活性成分是否是天然存在的，以及是否涉及特定的呋喃香豆素或黄酮类化合物。本文研究了非洛地平10 mg缓释片与250 ml市售葡萄柚汁、均质葡萄柚片、或相当于一个未加工的水果或Mater的无节部分的提取物。测定了呋喃香豆素类（香柠檬素、6 '，7'-环氧香柠檬素、6 '，7'-二羟基香柠檬素）和类黄酮（柚皮素光学异构体）对重组CYP 3A 4的抑制作用。在每个葡萄柚处理中测量呋喃香豆素和柚皮素前体（柚皮苷）浓度。结果：非洛地平AUC与商业葡萄柚汁、葡萄柚片段或葡萄柚提取物的平均3倍高于与水的。非洛地平峰浓度升高，但半衰期不变，脱氢非洛地平/非洛地平AUC比值降低。呋喃香豆素类化合物对CYP 3A 4具有竞争性抑制作用，其中佛手柑素的抑制作用最强。柚皮素异构体只产生竞争性抑制。佛手柑，6 '，7'-二羟基佛手柑，柚苷的浓度各不相同，葡萄柚治疗，但足以抑制显着在体外CYP 3A 4 activity.Conclusions：未经加工的葡萄柚可以引起药物相互作用与非洛地平，活性成分是天然存在的葡萄柚。香柠檬素可能在与商业葡萄柚汁的药物相互作用中很重要。6 '，7'-二羟基香柠檬素和柚皮苷可能在葡萄柚中更重要，因为它们的浓度更高。任何与商业葡萄柚汁药物相互作用的治疗问题现在应该扩展到包括整个水果和可能的葡萄柚皮制成的饮料。
Objectives: To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved.Methods: The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined after administration of felodipine 10 mg extended-release tablet with 250 mt commercial grapefruit juice, homogenized grapefruit segments, or extract of segment-free parts equivalent to one unprocessed fruit or mater in a randomized four-way crossover study. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin) and flavonoids (naringenin optical isomers) was determined. Furanocoumarin and naringenin precursor (naringin) concentrations were measured in each grapefruit treatment,Results: Felodipine AUC with commercial grapefruit juice, grapefruit segments, or grapefruit extract was on average 3-fold higher than that with water. Felodipine peak concentration was higher, but the half-life was unchanged, The dehydrofelodipine/felodipine AUC ratio was reduced. The furanocoumarins produced mechanism-based and competitive inhibition of CYP3A4, Bergamottin was the most potent mechanism-based inhibitor. Naringenin isomers produced only competitive inhibition. Bergamottin, 6',7'-dihydroxybergamottin, and naringin concentrations varied among grapefruit treatments but were sufficient to inhibit markedly in vitro CYP3A4 activity.Conclusions: Unprocessed grapefruit can cause a drug interaction with felodipine, The active ingredients are naturally occurring in the grapefruit. Bergamottin is likely important in drug interactions with commercial grapefruit juice. 6',7'-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations. Any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to include whole fruit and possibly confectioneries made from grapefruit peel.