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学科主题: 物理化学
题名: Detection and Identification of the Metabolites of Daphnetin in Rat Plasma by LC-ESI Tandem Mass Spectrometry
作者: Liang SC(梁思成) ;  Ge GB(葛广波) ;  Fang ZZ(房中则) ;  Dong PP(董佩佩) ;  Yang L(杨凌)
会议名称: 9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics
会议日期: 2010-9-4
出版日期: 2010-09-04
会议地点: TURKEY
通讯作者: Yang L
ISSN: 0360-2532
部门归属: 十八室
主办者: 国际药物代谢学会
摘要: Abstract: Metabolic profiles are pivotal to understand the mechanism of drug biotransformation and elimination, and sequential selection of suitable animal model(s) for pharmacokinetic, toxicological and pharmacological studies. Daphnetin (7,8-dihydroxycoumarin), is an oral medicine for treatment of coagulation disorders and rheumatoid arthritis in China and shows a rapid elimination in rats after intravenous administration with a t1/2 of approximately 15 min and poor bioavailability [1]. Recently, an in vitro study revealed that glucuronidation may play a role in daphnetin metabolism [2], but the in vivo metabolism of daphnetin remains unreported. Herein, we developed a MS-based method for characterization of the metabolites of daphnetin in rat plasma after oral administration at dose of 50 mg/kg bw. Fifteen minutes after daphnetin administration, seven metabolites but no parent were detected from rat plasma, indicating that the metabolism of daphnetin was extensively in rat. These metabolites were identified by comparison of their chromatographic behaviors and ESI-MS/MS spectra to those of daphnetin, an authentic standard 7-O-methyl-8-hydroxycoumarin and three biosynthesized standards, including 7-O glucuronide daphnetin, 8-O glucuronide daphnetin and 7-O-methyl-8-hydroxycoumarin glucuronide. The results showed that glucuronidation played a primary role in metabolic elimination of daphnetin in rat evidenced by the formation of two major monoglucuronides daphnetin (M-1 and M-2) and a diglucuronide daphnetin (M-3). The typical product ions for M-1 and M-2 were m/z 353 and 177, while M-3 showed the fragment ions of m/z 529, 353 and 177. Sulfotransferase(s) was also involved in the metabolism of daphnetin in rat, evidenced by the formation of two trace monosulfates daphnetin (M-4 and M-5) with fragment ions of m/z 257 and 177. Furthermore, glucuronidated (M-6) and sulfated (M-7) derivatives of 7-O-methyl-8-hydroxycoumarin were also detected in rat plasma with the fragment ions m/z 367 and 191 for M-6, and m/z 271 and 176 for M-7, which suggested the overlapping contribution of the conjugation pathways (glucuronidation, methoxylation and sulfation) in daphnetin elimination in rat. These data give us an insight into the mechanism of daphnetin metabolism and elimination, and provide useful information for improving the metabolic stability of this compound. References: 1. Qu SY, Wu YJ, Wang YH, and Zuo YX. Metabolism and pharmacokinetics of daphnetin. Yao Xue Xue Bao, 1983; 18: 496–500. 2. Liang SC, Ge GB, Liu HX, Zhang YY, et al. Identification and characterization of human UDP-glucuronosyltransferases responsible for the in vitro glucuronidation of daphnetin. Drug Metab Dispos, 2010; 38:973-980.
语种: 中文
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内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/114324
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Liang SC,Ge GB,Fang ZZ,et al. Detection and Identification of the Metabolites of Daphnetin in Rat Plasma by LC-ESI Tandem Mass Spectrometry[C]. 见:9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics. TURKEY. 2010-9-4.
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