A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A Inhibitors
A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A Inhibitors
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DOI：
10.1124/dmd.113.052563
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发表时间：
2013-09-01
影响因子：
3.9
通讯作者：
Paine, Mary F.
中科院分区：
文献类型：
--
作者：
Brantley, Scott J.;Graf, Tyler N.;Paine, Mary F.
尽管人们越来越认识到草药产品和传统药物之间潜在的不良相互作用，但对这些相互作用进行前瞻性评估的标准系统仍然难以捉摸。通过评估模型草药产品水飞蓟 (Silybum marianum) 与 CYP3A 探针底物咪达唑仑的药物相互作用责任，解决了这一信息差距。使用人肝脏和肠道微粒体筛选市售水飞蓟提取物和分离成分对咪达唑仑 1'-羟基化的抑制作用。相对于媒介物，100 μM 的水飞蓟素提取物和成分水飞蓟宾 A、异水飞蓟宾 A、异水飞蓟宾 B 和水飞蓟亭证明，至少一种微粒体制剂对 CYP3A 活性有 >50% 的抑制作用，从而促进了 IC50 测定。异水飞蓟宾 B 和水飞蓟亭的 IC(50) 值分别为 60 和 90 μM，而其余成分的 IC(50) 值 >100 μM。当作为潜在的基于机制的抑制剂进行测试时，含有 1,4-二恶烷部分的提取物和成分的 IC50 变化 > 1.5 倍。半纯化提取物水飞蓟宾和两种相关成分（水飞蓟宾 A 和水飞蓟宾 B）表现出对重组 CYP3A4 的基于机制的抑制（K-I，类似于 100 mu M；k（无活性），类似于 0.20 min(-1)），但不抑制微粒体 CYP3A 活性。使用静态力学方程和重组 CYP3A4 数据预测咪达唑仑曲线下面积的最大增加为 1.75 倍，这可能需要临床评估。除了市售提取物之外，对单一草药产品成分的相互作用倾向的评估将能够阐明潜在的具有临床意义的草药-药物相互作用的机制。将该框架应用于其他草药产品将允许预测草药-药物相互作用并有助于确定临床评估的优先顺序。
Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1'-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 mu M demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC(50)s for isosilybin B and silychristin were similar to 60 and 90 mu M, respectively, whereas those for the remaining constituents were >100 mu M. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a > 1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (K-I, similar to 100 mu M; k(inact), similar to 0.20 min(-1)) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.