Satoh Takashi, Igarashi Ayaka, Tanno Misaki, Yamada Koki, Takahashi-Suzuki Natsuko, Watanabe Kazuhiro
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science.
J Pharm Pharm Sci. 2018;21(1):195-206. doi: 10.18433/jpps29783.
The chemotherapeutic agent irinotecan is hydrolyzed to its active form SN-38 by human carboxyesterases, but SN-38 is converted into the inactive form SN-38G by hepatic UDP-glucuronosyltransferases (UGTs). The aim of the present study was to evaluate the inhibitory effects of two b-glucuronidase-treated Japanese traditional herbal medicines (kampo), Hange-Shashin-To (TJ-14) and Sairei-To (TJ-114) on SN-38 glucuronidation, and the deglycosylation of baicalin (BG) and glycyrrhizic acid (GL) derived from TJ-14 and TJ-114 to form their respective aglycones, baicalein (BA) and glycyrrhetinic acid (GA).
The inhibitory effects of b-glucuronidase-treated TJ-14 and TJ-114 on SN-38 glucuronidation by human liver microsomes were examined. BA and GA, which were enzymatically converted from BG and GL present in TJ-14 and TJ-114, were examined in the same manner. Furthermore, the enzymatic activities were measured by using recombinant UGT1A1 and UGT1A9 isoforms instead of human liver microsomes. BA, GA, SN-38, and their glycosides/glucuronides were analyzed with an LC-MS system.
As regards the linear initial reaction rate, SN-38 glucuronidation by human liver microsomes was significantly inhibited by the addition of b-glucuronidase-untreated TJ-14 and TJ-114, but was more strongly inhibited by the addition of b-glucuronidase-treated TJ-14 and TJ-114. The results of LC-MS analysis and pharmacokinetic studies suggested that BA is the main inhibitor of SN-38 glucuronidation. In the Dixon plot, BA showed competitive inhibition of SN-38 glucuronidation, and the inhibition constant was 8.70 ± 3.24 mM. Previous reports, studies of recombinant UGT isoforms indicated that SN-38 glucuronidation was mainly catalyzed by UGT1A1.
These findings strongly suggested that SN-38 glucuronidation is inhibited by BA. BA could act as a pharmacokinetic regulating factor associated with SN-38 glucuronidation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
化疗药物伊立替康被人羧酸酯酶水解为其活性形式SN - 38，但SN - 38被肝脏尿苷二磷酸葡萄糖醛酸转移酶（UGTs）转化为无活性形式SN - 38G。本研究的目的是评估两种经β - 葡萄糖醛酸酶处理的日本传统草药方剂（汉方），柴胡桂枝干姜汤（TJ - 14）和柴苓汤（TJ - 114）对SN - 38葡萄糖醛酸化的抑制作用，以及TJ - 14和TJ - 114中黄芩苷（BG）和甘草酸（GL）去糖基化形成其各自苷元黄芩素（BA）和甘草次酸（GA）的情况。
检测经β - 葡萄糖醛酸酶处理的TJ - 14和TJ - 114对人肝微粒体SN - 38葡萄糖醛酸化的抑制作用。以同样方式检测TJ - 14和TJ - 114中存在的BG和GL酶促转化生成的BA和GA。此外，使用重组UGT1A1和UGT1A9同工型代替人肝微粒体测量酶活性。用液相色谱 - 质谱系统分析BA、GA、SN - 38及其糖苷/葡萄糖醛酸苷。
就线性初始反应速率而言，未添加β - 葡萄糖醛酸酶处理的TJ - 14和TJ - 114可显著抑制人肝微粒体对SN - 38的葡萄糖醛酸化，而添加经β - 葡萄糖醛酸酶处理的TJ - 14和TJ - 114时抑制作用更强。液相色谱 - 质谱分析和药代动力学研究结果表明BA是SN - 38葡萄糖醛酸化的主要抑制剂。在迪克森图中，BA对SN - 38葡萄糖醛酸化表现出竞争性抑制作用，抑制常数为8.70±3.24 mM。先前的报道，对重组UGT同工型的研究表明SN - 38葡萄糖醛酸化主要由UGT1A1催化。
这些发现有力地表明BA可抑制SN - 38葡萄糖醛酸化。BA可能作为与SN - 38葡萄糖醛酸化相关的药代动力学调节因子。本文接受发表后评论。注册读者（见“致读者”）可通过点击本期目录页上的摘要进行评论。
