School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
J Ethnopharmacol. 2012 Jun 1;141(2):742-53. doi: 10.1016/j.jep.2011.08.042. Epub 2011 Aug 26.
Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (-)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models.
Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose-response curves were plotted and IC(50) values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb-drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples.
It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites.
Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb-drug and herb-herb interactions between B and selected compounds, especially CUR.
黄芩素（B）是一种从传统中药黄芩的根中分离出来的生物活性黄酮，在吸收过程中被发现会经历广泛的肠道二期代谢。与 B 具有相同代谢途径的化合物或 UGT 和 SULT 酶的抑制剂，预计会干扰 B 的代谢，导致 B 的吸收改变。本研究旨在使用体外和原位模型，鉴定 B 与四种选定化合物（对乙酰氨基酚（APAP）、（-）表儿茶素（EC）、胡椒碱（PIP）和姜黄素（CUR））之间潜在的肠道吸收和代谢相互作用。
使用三种体外和一种原位方法研究选定化合物对 B 的代谢和吸收的影响。使用大鼠肠 s9 和 Caco-2 细胞裂解物进行孵育研究，以研究选定化合物对 B 葡萄糖醛酸化和硫酸化的影响。绘制了 sigmoidal 剂量反应曲线，并估算了 IC50 值。还使用 Caco-2 细胞单层模型进行了从顶侧向基底侧的吸收研究，以研究选定化合物对 B 吸收的影响。鉴定出最有效的抑制剂，并用原位大鼠肠灌注模型进一步研究其与 B 潜在的草药-药物相互作用。LC/MS/MS 用于收集样品中 B 及其代谢物的分析。
发现所有四种选定的化合物都能对 B 的葡萄糖醛酸化和硫酸化产生剂量依赖性抑制。此外，CUR 和高剂量 EC 的存在显示出 B 吸收的后续增加。一般来说，葡萄糖醛酸化抑制的效力顺序为：CUR>PIP>EC>APAP；而硫酸化抑制的效力顺序为：CUR>EC>PIP>APAP。选择 CUR 进一步使用原位大鼠肠灌注模型研究其对 B 的体内影响。结果发现，CUR 通过抑制其代谢物的形成，可显著增加 B 的吸收。
我们的研究结果表明，B 的肠道代谢可能会被所有选定的化合物抑制，其中 CUR 是最有效的抑制剂，这可能导致 B 的吸收增加。本研究对进一步研究 B 与选定化合物（特别是 CUR）之间的草药-药物和草药-草药相互作用的体内评价具有重要意义。
