Grapefruit Juice and its Constituents Augment Colchicine Intestinal Absorption: Potential Hazardous Interaction and the Role of P-Glycoprotein
Grapefruit Juice and its Constituents Augment Colchicine Intestinal Absorption: Potential Hazardous Interaction and the Role of P-Glycoprotein
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DOI：
10.1007/s11095-008-9789-7
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发表时间：
2009-04-01
影响因子：
3.7
通讯作者：
Amidon, Gordon L.
中科院分区：
文献类型：
--
作者：
Dahan, Arik;Amidon, Gordon L.
为了研究口服微管聚合抑制剂秋水仙碱（P-gp和CYP 3A 4底物）与葡萄柚汁（GFJ）之间的相互作用，在不存在或存在已知P-gp抑制剂（维拉帕米和奎尼丁）的情况下，研究了秋水仙碱在Caco-2细胞单层中的AP-BL和BL-AP方向转运。研究了GFJ及其主要成分（6 '-7'-二羟基香柠檬素、柚皮苷和柚皮素）对秋水仙碱Caco-2粘膜分泌的浓度依赖性作用。然后在大鼠空肠和回肠灌注模型中原位研究GFJ对秋水仙碱渗透性的影响，秋水仙碱表现出比AP-BL Caco-2渗透性高20倍的BL-AP渗透性，表明净粘膜分泌，其被维拉帕米/奎尼丁减少。GFJ以浓度依赖性方式增加秋水仙碱AP-BL渗透性，降低BL-AP渗透性（IC 50值分别为0.75%和0.46%），表明抑制外排转运，而不是代谢酶。在用GFJ进行实验前孵育后获得了类似的效果，即使在整个经上皮研究中不存在汁液。6 '-7'-二羟基香柠檬素、柚皮苷和柚皮素对秋水仙碱BL-AP分泌表现出浓度依赖性抑制（IC 50值分别为90、592和11.6 μ M）。10%的GFJ使秋水仙碱大鼠原位回肠的通透性增加一倍，空肠的通透性增加1.5倍。由于秋水仙碱的治疗指数狭窄和严重的毒副作用，这种相互作用的意识是谨慎的。
To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate.Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum.Colchicine exhibited 20-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP-BL permeability was increased and BL-AP was decreased by GFJ in a concentration-dependent manner (IC50 values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6'-7'-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL-AP secretion (IC50 values of 90, 592 and 11.6 mu M respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability.The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.