雷公藤甲素衍生物雷腾舒的体外代谢研究 : = Studies on the metabolism of a triptolide derivative(5R)-5-hydroxytriptolide in vitro
本课题的目的是研究雷公藤甲素衍生物雷腾舒的体外代谢特征。将雷腾舒分别与人、猴、犬、大鼠或小鼠的肝细胞一起孵育,共鉴定出4个代谢物,分别为环氧水解开环代谢物(M1)、谷胱甘肽结合代谢物(M2)和单氧化并谷胱甘肽结合代谢物(M3-1和M3-2)。在人或大鼠肝微粒体孵育体系中,共鉴定出7个代谢物,分别为脱氢代谢物(M4)和单氧化代谢物(M5-1～M5-6)。通过化学半合成和大鼠原代肝细胞孵育的方法获得代谢物的对照品,并与以上代谢物相比对,确认了5个代谢物的结构,分别为12,13-环氧水解开环代谢物M1、12-谷胱甘肽结合代谢物M2、(16S)-单羟基化代谢物M5-1、(2R)-单羟基化代谢物M5-4和(19R)-单羟基化代谢物M5-5。体外活性评价显示,仅(2R)-羟基化代谢物表现出弱的免疫抑制活性,其活性不足母体药物的十分之一,同时毒性也显著降低。提示雷腾舒可能在体内经历代谢失活和减毒。.
The purpose of current study is to investigate the metabolic profile of a triptolide derivative(5R)-5-hydroxytriptolide in vitro.(5R)-5-Hydroxytriptolide was incubated with the hepatocytes of human, monkey, dog,rat or mouse, respectively. Compared with inactivated hepatocytes, four metabolites were identified in hepatocytes from all five species: oxidative ring-opening metabolite(M1), glutathione-conjugating metabolite(M2), and monooxidative combined with glutathione-conjugating metabolites(M3-1 and M3-2), respectively. In human or rat liver microsomes, seven metabolites of(5R)-5-hydroxytriptolide were found, dehydrogenated metabolite(M4) and monooxidative metabolites(M5-1–M5-6), respectively. Reference standards for the metabolites were obtained either through chemical semisynthesis or biotransformation through rat primary hepatocytes. The structures of five metabolites were confirmed, which were 12,13-epoxy ring-opening metabolite M1, 12-glutathione-conjugating metabolite M2,(16S)-,(2R)-and(19 R)-monohydroxylated metabolites M5-1, M5-4, and M5-5, respectively.In vitro activity assay revealed that only(2R)-hydroxylated metabolite exhibited weak immunosuppressive activity with less than one-tenth the activity of its parent drug, and a significant decrease in toxicity was observed. It is suggested that(5R)-5-hydroxytriptolide might undergo metabolic inactivation and detoxification in vivo..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019-07-12 14:39 2019 |
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| Erschienen: |
2019-07-12 14:39 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2019 |
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| Enthalten in: |
Yao xue xue bao - (2019), 08 vom: 12 14:39. Juli, Seite 1484-1492 Original Letters: Enthalten in 药学学报 (DE-600)2994062-X (DE-600)2994062-X 北京市 |
| Reihe: |
China Academic Journals (CAJ), E, 医药卫生科技 = Medicine & Public Health |
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| Sprache: |
Chinesisch |
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| Weiterer Titel: |
Studies on the metabolism of a triptolide derivative(5R)-5-hydroxytriptolide in vitro |
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| Beteiligte Personen: |
徐叶 [VerfasserIn] |
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| Links: |
oversea.cnki.net [lizenzpflichtig] |
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| Anmerkungen: |
Author info:XU Ye;DU Jiang-bo;FENG Hui-jin;ZUO Jian-ping;XU Hong-tao;LI Yuan-chao;ZHONG Da-fang;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences;University of Chinese Academy of Sciences |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
CAJ637348311 |
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| 520 | |a 本课题的目的是研究雷公藤甲素衍生物雷腾舒的体外代谢特征。将雷腾舒分别与人、猴、犬、大鼠或小鼠的肝细胞一起孵育,共鉴定出4个代谢物,分别为环氧水解开环代谢物(M1)、谷胱甘肽结合代谢物(M2)和单氧化并谷胱甘肽结合代谢物(M3-1和M3-2)。在人或大鼠肝微粒体孵育体系中,共鉴定出7个代谢物,分别为脱氢代谢物(M4)和单氧化代谢物(M5-1～M5-6)。通过化学半合成和大鼠原代肝细胞孵育的方法获得代谢物的对照品,并与以上代谢物相比对,确认了5个代谢物的结构,分别为12,13-环氧水解开环代谢物M1、12-谷胱甘肽结合代谢物M2、(16S)-单羟基化代谢物M5-1、(2R)-单羟基化代谢物M5-4和(19R)-单羟基化代谢物M5-5。体外活性评价显示,仅(2R)-羟基化代谢物表现出弱的免疫抑制活性,其活性不足母体药物的十分之一,同时毒性也显著降低。提示雷腾舒可能在体内经历代谢失活和减毒。 | ||
| 520 | |a The purpose of current study is to investigate the metabolic profile of a triptolide derivative(5R)-5-hydroxytriptolide in vitro.(5R)-5-Hydroxytriptolide was incubated with the hepatocytes of human, monkey, dog,rat or mouse, respectively. Compared with inactivated hepatocytes, four metabolites were identified in hepatocytes from all five species: oxidative ring-opening metabolite(M1), glutathione-conjugating metabolite(M2), and monooxidative combined with glutathione-conjugating metabolites(M3-1 and M3-2), respectively. In human or rat liver microsomes, seven metabolites of(5R)-5-hydroxytriptolide were found, dehydrogenated metabolite(M4) and monooxidative metabolites(M5-1–M5-6), respectively. Reference standards for the metabolites were obtained either through chemical semisynthesis or biotransformation through rat primary hepatocytes. The structures of five metabolites were confirmed, which were 12,13-epoxy ring-opening metabolite M1, 12-glutathione-conjugating metabolite M2,(16S)-,(2R)-and(19 R)-monohydroxylated metabolites M5-1, M5-4, and M5-5, respectively.In vitro activity assay revealed that only(2R)-hydroxylated metabolite exhibited weak immunosuppressive activity with less than one-tenth the activity of its parent drug, and a significant decrease in toxicity was observed. It is suggested that(5R)-5-hydroxytriptolide might undergo metabolic inactivation and detoxification in vivo. | ||
| 610 | 2 | 4 | |a 中国科学院上海药物研究所新药研究国家重点实验室 |
| 610 | 2 | 4 | |a 中国科学院大学 |
| 650 | 4 | |a 中药学、方剂学 | |
| 650 | 4 | |a 中医 | |
| 650 | 4 | |a 医药、卫生 | |
| 650 | 4 | |a Traditional Chinese Medicinal Herbs | |
| 650 | 4 | |a 医药卫生科技 | |
| 650 | 4 | |a Medicine & Public Health | |
| 650 | 4 | |a 雷腾舒 | |
| 650 | 4 | |a 药物代谢 | |
| 650 | 4 | |a 代谢物鉴定 | |
| 650 | 4 | |a 肝细胞 | |
| 650 | 4 | |a 肝微粒体 | |
| 650 | 4 | |a (5R)-5-hydroxytriptolide | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a metabolite confirmation | |
| 650 | 4 | |a hepatocytes | |
| 650 | 4 | |a liver microsomes | |
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