In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts
In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts
复制标题
DOI：
10.1016/j.jep.2013.10.029
复制
发表时间：
2013-12-12
影响因子：
5.4
通讯作者：
Foster, Brian C.
中科院分区：
文献类型：
--
作者：
Cieniak, Carolina;Liu, Rui;Foster, Brian C.
民族药理学相关性：传统药物和传统医学疗法之间的相互作用可能会影响药物疗效，并增加不良反应的可能性。克里传统的治疗是全面的，病人可以使用药用植物与传统药物同时使用。然而，这些药用植物可能与药物相互作用的信息有限，需要更多的机制信息。在这项研究中，评估了传统使用的克里植物提取物的潜在相互作用，这种相互作用可能会改变两种降血糖药物格列齐特的分布（达美康）和瑞格列奈通过抑制代谢或跨细胞膜转运来抑制（葡糖醛酸）。通过HPLC和单个细胞色素P450 2C 9，2C 19，2C 8和3A 4在微孔板荧光测定中的结果。在荧光测定法中还检查了格列齐特、土大黄素及其苷元衍生物、土大黄素。运输的影响进行了检查，11提取物使用肠上皮Caco-2分化细胞单层模型的时间长达180分钟。结果：两种降糖药物，格列齐特和瑞格列奈穿越Caco-2单层的时间依赖性的方式，不受Cree植物提取物。在人肝微粒体试验中，Cree植物提取物的孵育抑制了CYP 2C 9、2C 19、2C 8和3A 4介导的代谢，以及4种瑞格列奈代谢产物的形成：M4、m/z 451-A、m/z 451-B和瑞格列奈的葡糖苷酸。格列齐特无明显抑制作用。同样，土大黄素对酶的影响很小，导致的变化小于10%，但对CYP 2C 19的抑制率为17%。相比之下，苷元大黄素对所有CYP介导的代谢的影响最大。其抑制范围为平均58%的CYP 3A 4抑制至89%的CYP 2C 9抑制。虽然土大黄素和苷元对瑞格列奈代谢没有显著影响，但它们对格列齐特代谢有抑制作用。苷元显着影响格列齐特及其代谢产物的水平。结论：这些研究表明，Cree植物提取物检查有可能在体外引起药物相互作用，通过对关键代谢酶的影响。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: Interactions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes.Materials and methods: The effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180 min.Results: Both blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites.Conclusion: These studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes. (C) 2013 Elsevier Ireland Ltd. All rights reserved.