Zhang Hui, Zhao Zhenying, Wang Tao, Wang Yijia, Cui Xiao, Zhang Huijuan, Fang Zhong-Ze
Department of Pharmacy, the Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou, Zhejiang Province, P.R China.
School of Chemical Engineering and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, P.R China.
Phytother Res. 2016 Jul;30(7):1189-96. doi: 10.1002/ptr.5627. Epub 2016 May 4.
Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, respectively. Based on the inhibition evaluation standard ([I]/Ki < 0.1, low possibility; 0.1 < [I]/Ki < 1, medium possibility; [I]/Ki > 1, high possibility), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd.
牛蒡子苷是牛蒡子的主要药理成分，而牛蒡子苷元是牛蒡子苷经人肠道细菌催化形成的代谢产物。本研究旨在探究牛蒡子苷和牛蒡子苷元对重要的Ⅱ相药物代谢酶尿苷二磷酸葡萄糖醛酸转移酶（UGTs）的抑制情况，以表明可能存在的药草-药物相互作用。体外筛选实验表明，100μM的牛蒡子苷和牛蒡子苷元可抑制UGT1A3、1A9、2B7和2B15的活性。基于同源建模的牛蒡子苷和牛蒡子苷元与UGT2B15活性腔的计算机模拟对接显示，氢键和疏水相互作用导致牛蒡子苷（-8.14 kcal/mol）和牛蒡子苷元（-8.43 kcal/mol）与UGT2B15具有较强的结合自由能。抑制动力学研究表明，牛蒡子苷和牛蒡子苷元分别对UGT2B15表现出竞争性和非竞争性抑制作用。计算得出牛蒡子苷和牛蒡子苷元抑制UGT2B15的抑制动力学参数（Ki）分别为16.0和76.7μM。根据给予100mg/kg牛蒡子苷后牛蒡子苷和牛蒡子苷元的血浆浓度，计算得出牛蒡子苷和牛蒡子苷元的[I]/Ki值分别为0.3和0.007。根据抑制评估标准（[I]/Ki＜0.1，可能性低；0.1＜[I]/Ki＜1，可能性中等；[I]/Ki＞1，可能性高），牛蒡子苷可能中等程度地诱导药物-药物相互作用。基于这些结果，临床监测牛蒡子的使用非常重要且必要。版权所有©2016约翰威立父子有限公司。
