UGT-mediated metabolism plays a dominant role in the pharmacokinetic behavior and the disposition of morusin in vivo and in vitro
UGT-mediated metabolism plays a dominant role in the pharmacokinetic behavior and the disposition of morusin in vivo and in vitro
复制标题
UGT 介导的代谢在 Morusin 的药代动力学行为和体内外处置中起主导作用
DOI：
10.1016/j.jpba.2018.02.062
复制
发表时间：
2018-05-30
影响因子：
3.4
通讯作者：
Tang, Lan
中科院分区：
文献类型：
--
作者：
Hou, Chuqi;Liu, Wenqin;Tang, Lan
桑色素是从桑葚的分支和根皮中分离得到的异戊烯化黄酮，具有多种药理活性。然而，缺乏对它的吸收和处置的广泛研究。本文研究了桑色素在大鼠体内的药代动力学行为及其在体首过代谢。通过12种人重组UDP-葡萄糖醛酸转移酶（UGT）、9种CYP 450以及肝和肠微粒体进一步研究了桑色素的代谢途径。通过LC-MS/MS法在大鼠肠道和胆汁中鉴别出4种单葡糖苷酸代谢产物（M-5-G、M-4 '-G、M-2'-G和M11-2），同时在血浆中也检测到其中3种（M-5-G、M-4 '-G和M11- 2）。M-4 '-G是主要的共轭物。然而，在大鼠肠道和胆汁中发现的CYP 450代谢物很少。大鼠血浆中仅检测到少量M1-1。UGT 1A 1、1A 3、1A 7和2B 7是桑色素葡萄糖醛酸化的主要贡献者。桑色素在所有UGT中均表现出底物抑制动力学特征。HLM、RLM、UGT 1A 1、UGTIA 3和UGT 2B 7中M-4 '-G的清除率分别为137.02、127.55、32.54、41.18和35.07 ml/min/mg。此外，CYP 3A 5、3A 4和2C 19主要参与桑色素的氧化代谢。桑色素及其偶联物的药代动力学曲线呈双峰型，可能存在肠肝循环。结果表明，桑色素在体内的主要代谢途径为葡萄糖醛酸化，M-4 '-G是桑色素的主要代谢产物。(C)2018爱思唯尔B. V.保留所有权利。
Morusin is a prenylated flavone isolated from mulberry, the branch and root bark of various Morus species, which possesses diverse pharmacological activities. However, it lacks extensive studies about its absorption and disposition. This study investigated the pharmacokinetic behavior of morusin in rat, and its first-pass metabolism in situ. The metabolic pathway of morusin was further investigated by 12 human recombinant UDP-glucuronosyltransferases (UGTs), 9 CYP450s, as well as liver and intestinal microsomes. Four mono-glucuronide metabolites (M-5-G, M-4'-G, M-2'-G, and M11-2) were identified in rat intestine and bile by LC-MS/MS, while three of them were also detected in plasma (M-5-G, M-4'-G, and M11-2). M-4'-G was the principal conjugate. However, few CYP450 metabolites were found in rat intestine and bile. Only a small amount of M1-1 could be detected in rat plasma. UGT1A1, 1A3, 1A7, and 2B7 were the major contributors to morusin glucuronidation. Morusin exhibited substrate inhibition kinetic characteristics in all UGTs. Clearance rates of M-4'-G in HLM, RLM, UGT1A1, UGTIA3, and UGT2B7 were 137.02,127.55, 32.54, 41.18, and 35.07 ml/min/mg, respectively. Besides, CYP3A5, 3A4, and 2C19 primarily contributed to the oxidative metabolism of morusin. The pharmacokinetic curves of morusin and its conjugates presented double peaks, showing that an enterohepatic recycling may exist. In conclusion, glucuronidation was confirmed to be the crucial metabolic pathway for morusin in vivo, and M-4'-G was the main metabolite. (C) 2018 Elsevier B.V. All rights reserved.