Fuhr U, Kummert A L
Department of Clinical Pharmacology, University Hospital Frankfurt am Main, Germany.
Clin Pharmacol Ther. 1995 Oct;58(4):365-73. doi: 10.1016/0009-9236(95)90048-9.
The increase of concentrations observed for many drugs when administered concomitantly with grapefruit juice was attributed to inhibition of cytochrome P450 enzymes by naringenin, the aglycone of the grapefruit flavonoid naringin. However, this explanation is equivocal, and formation of naringenin after ingestion of grapefruit juice has not been proved. We investigated renal excretion of naringin, naringenin, and its glucuronides after administration of 20 ml grapefruit juice (621 mumol/L naringin) per kilogram of body weight to six healthy adults. Urine was collected for 24 hours, and flavonoids were measured by HPLC in aliquots with and without glucuronidase pretreatment. Naringin or naringin glucuronides were not found. Naringenin and its glucuronides appeared in urine after a median lag-time of 2 hours and reached 0.012% to 0.37% and 5.0% to 57%, respectively, of the molar naringin dose. In additional investigations, low concentrations (< 4 mumol/L) of naringenin glucuronides, but neither naringin nor naringenin were found in plasma samples from previous grapefruit juice interaction studies, and metabolization of naringin to naringenin occurred during 24 hours of incubation (37 degrees C) in three of five feces samples tested. The data suggest that cleavage of the sugar moiety, presumably by intestinal bacteria, is the first step of naringin metabolism. Naringenin formation is thought to be the crucial step in determination of bioavailability of the compound, which undergoes rapid glucuronidation. The pronounced interindividual variability of naringin kinetics provides a possible explanation for some of the apparently contradictory results of drug interaction studies with grapefruit and naringin.
许多药物与葡萄柚汁同时服用时观察到的浓度增加，归因于柚皮苷（葡萄柚类黄酮柚皮苷的苷元）对细胞色素P450酶的抑制作用。然而，这种解释并不明确，且摄入葡萄柚汁后柚皮苷元的形成尚未得到证实。我们对6名健康成年人每千克体重给予20毫升葡萄柚汁（621微摩尔/升柚皮苷）后，研究了柚皮苷、柚皮苷元及其葡糖醛酸苷的肾排泄情况。收集24小时尿液，通过高效液相色谱法在有和没有葡糖醛酸酶预处理的等分试样中测量类黄酮。未发现柚皮苷或柚皮苷葡糖醛酸苷。柚皮苷元及其葡糖醛酸苷在中位滞后时间2小时后出现在尿液中，分别达到柚皮苷摩尔剂量的0.012%至0.37%和5.0%至57%。在进一步的研究中，在先前葡萄柚汁相互作用研究的血浆样本中未发现低浓度（<4微摩尔/升）的柚皮苷元葡糖醛酸苷，但未发现柚皮苷和柚皮苷元，并且在测试的五份粪便样本中的三份中，柚皮苷在37℃孵育24小时期间发生了向柚皮苷元的代谢。数据表明，糖部分的裂解可能由肠道细菌引起，是柚皮苷代谢的第一步。柚皮苷元的形成被认为是决定该化合物生物利用度的关键步骤，该化合物会迅速进行葡糖醛酸化。柚皮苷动力学明显的个体间变异性为一些与葡萄柚和柚皮苷的药物相互作用研究中明显矛盾的结果提供了一种可能的解释。
