Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry
Autor: | Dafang Zhong, Xiaoyan Chen, Pan Deng, Tian Geng You, Tao Yuan, Hai Hua Huang |
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Rok vydání: | 2011 |
Předmět: |
Male
Metabolite Glucuronidation Amiodarone Pharmaceutical Science In Vitro Techniques Mass Spectrometry Hydroxylation chemistry.chemical_compound Bile Humans Chromatography High Pressure Liquid Aged Alcohol dehydrogenase Aged 80 and over Pharmacology Chromatography Molecular Structure biology Metabolism Metabolic pathway chemistry Biochemistry S9 fraction Inactivation Metabolic Microsomes Liver biology.protein Microsome Female Anti-Arrhythmia Agents |
Zdroj: | Drug Metabolism and Disposition. 39:1058-1069 |
ISSN: | 1521-009X 0090-9556 |
Popis: | 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 ω-carboxylate amiodarone (M12). Metabolite M12 was isolated from human bile, and the chemical structure was confirmed using UPLC-Q/TOF MS and ¹H 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 ω-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 ω-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. |
Databáze: | OpenAIRE |
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