Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry
文献类型：期刊论文
| 作者 | Deng, Pan2; You, Tiangeng1; Chen, Xiaoyan2 ; Yuan, Tao2; Huang, Haihua2; Zhong, Dafang2
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2011-06 |
| 卷号 | 39期号:6页码:1058-1069 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.110.037671 |
| 文献子类 | Article |
| 英文摘要 | Amiodarone is recognized as an effective drug in the treatment of arrhythmias. Previous experiments demonstrated that mono-N-desethylamiodarone (MDEA) was the major circulating metabolite in humans. In addition, dealkylation, hydroxylation, and deamination were minor metabolic pathways. The purpose of this study was to identify the metabolites of amiodarone in the bile obtained from patients with T-tube drainage after oral drug administration. Amiodarone metabolism in vitro was also investigated using human liver microsomes (HLMs) and S9 fraction. Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) revealed 33 metabolites in human bile, including 22 phase I and 11 phase II metabolites. The major metabolites were MDEA (M7) and omega-carboxylate amiodarone (M12). Metabolite M12 was isolated from human bile, and the chemical structure was confirmed using UPLC-Q/TOF MS and H-1 NMR. Moreover, the authentic standards of two hydroxylated metabolites, 2-hydroxylamiodarone and 3'-hydroxylamiodarone, were obtained through microbial transformation. Several novel metabolic pathways of amiodarone in human were proposed, including omega-carboxylation, deiodination, and glucuronidation. The in vitro study demonstrated that incubation of HLMs with amiodarone did not give rise to any carboxyl metabolites. In contrast, M12 and its metabolites were detected in human liver S9 incubation samples, and the production of these metabolites were inhibited almost completely by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, suggesting the involvement of alcohol dehydrogenase in the omega-carboxylation of amiodarone. Overall, UPLC-Q/TOF MS analysis leads to the discovery of several novel amiodarone metabolites in human bile and underscores the importance of bile as an excretion pathway. |
| WOS关键词 | N-DESETHYLAMIODARONE ; THYROID-DYSFUNCTION ; TREATED PATIENTS ; IODINE INTAKE ; PHARMACOKINETICS ; LIVER ; RAT ; PLASMA |
| 资助项目 | National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program," China[2009ZX09301-001] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000290620000017 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278521]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Zhong, Dafang |
| 作者单位 | 1.Shanghai E Hosp, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Deng, Pan,You, Tiangeng,Chen, Xiaoyan,et al. Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry[J]. DRUG METABOLISM AND DISPOSITION,2011,39(6):1058-1069. |
| APA | Deng, Pan,You, Tiangeng,Chen, Xiaoyan,Yuan, Tao,Huang, Haihua,&Zhong, Dafang.(2011).Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry.DRUG METABOLISM AND DISPOSITION,39(6),1058-1069. |
| MLA | Deng, Pan,et al."Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry".DRUG METABOLISM AND DISPOSITION 39.6(2011):1058-1069. |
入库方式： OAI收割
来源：上海药物研究所
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