Runkel M, Tegtmeier M, Legrum W
Department of Toxicology and Pharmacology, Philipps-University, Marburg, Germany.
Eur J Clin Pharmacol. 1996;50(3):225-30. doi: 10.1007/s002280050097.
Grapefruit juice is known to inhibit mammalian cytochrome P450 isozymes such as CYP3A4. The aim of this study was to investigate the influence of the juice on the fate of coumarin (1,2-benzopyrone) metabolized by CYP2A6 in man. Its potentially inhibitory effect was examined when low and high amounts of grapefruit juice were taken.
In crossover studies, doses of 10 mg coumarin (Venalot) were given orally to an healthy male volunteer. The drug was taken either with water or with grapefruit juice, at different volumes (300 ml or 4 x 250 ml at intervals of 30 min). Urine samples were collected up to 24 h after dosing. After in vitro hydrolysis they were analysed fluorimetrically for umbelliferone, the metabolite of coumarin, and cumulative excretion curves were established. HPLC and TLC served to identify fluorescent metabolites from the juice.
If coumarin is given in water its excretion is complete after 6 h and 70% of the dose is recovered. Grapefruit juice (300 ml) given simultaneously slightly retards the appearance of the fluorescent metabolite in the urine within the first few hours. The recovery of coumarin remains unaffected. One litre of juice enhances the delay and increases the recovery of coumarin to nearly 100%. Respective controls with grapefruit juice alone lead to remarkable excretions of a fluorescent material identified as conjugated scopoletin, which strongly interferes with the analysis of the coumarin experiment. The precursor of scopoletin is widely present at different concentrations in commercially available grapefruit juices. However, the autoinhibition of the juice is correlated neither to the concentration of naringin nor to that of scopoletin.
Only grapefruit juice given at high doses (1 L) retards the appearance of the main metabolite of coumarin administered orally but increases its recovery. Due to scopoletin formed from the grapefruit juice, experiments especially with coumarin are strongly affected.
已知葡萄柚汁可抑制哺乳动物细胞色素P450同工酶，如CYP3A4。本研究旨在调查葡萄柚汁对人肝脏中由CYP2A6代谢的香豆素（1,2-苯并吡喃酮）代谢情况的影响。研究了饮用少量和大量葡萄柚汁时其潜在的抑制作用。
在交叉研究中，给一名健康男性志愿者口服10mg香豆素（Venalot）。药物用水或葡萄柚汁送服，葡萄柚汁的服用量不同（300ml或4×250ml，间隔30分钟）。给药后24小时内收集尿液样本。体外水解后，用荧光法分析尿液中香豆素的代谢产物伞形酮，并绘制累积排泄曲线。用高效液相色谱法（HPLC）和薄层色谱法（TLC）鉴定葡萄柚汁中的荧光代谢产物。
香豆素用水送服时，6小时后排泄完毕，回收剂量占给药剂量的70%。同时饮用300ml葡萄柚汁会在最初几小时内略微延迟尿液中荧光代谢产物的出现。香豆素的回收率不受影响。饮用1升葡萄柚汁会增强延迟作用，并使香豆素的回收率增加至近100%。单独饮用葡萄柚汁的相应对照导致一种鉴定为结合型东莨菪亭的荧光物质大量排泄，这严重干扰了香豆素实验的分析。东莨菪亭的前体在市售葡萄柚汁中广泛存在，浓度各异。然而，葡萄柚汁的自身抑制作用与柚皮苷或东莨菪亭的浓度均无关联。
仅高剂量（1升）的葡萄柚汁会延迟口服香豆素主要代谢产物的出现，但会增加其回收率。由于葡萄柚汁中形成的东莨菪亭，尤其是涉及香豆素的实验会受到严重影响。
