High-performance liquid chromatographic isolation and fast atom bombardment mass spectrometric identification of di-N-desethylamiodarone, a new metabolite of amiodarone in the dog

Latini, Roberto; Reginato, R.; Burlingame, Alma L.; Kates, Robert E.

doi:10.1002/bms.1200110906

Cited by 24 publications

(3 citation statements)

References 5 publications

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“…Although the LD 50 for primary rat hepatocytes was slightly lower compared with the LD 50 for HepG2 cells, both of these values were considerably greater than the mean plasma amiodarone concentration of 0.53 M determined for mice treated with 150 mg/kg amiodarone for 4 days. The major metabolite of amiodarone in humans is DEA (Latini et al, 1984). Similar to the effects of amiodarone, DEA treatment caused a dose-dependent toxicity, but with a lower apparent LD 50 of 9 M in HepG2 cells and 10 M in primary rat hepatocytes.…”

Section: Resultsmentioning

confidence: 97%

Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-αTarget Gene Activation

McCarthy

Pollak²,

Hanniman³

et al. 2004

J Pharmacol Exp Ther

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Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-␣ (PPAR␣), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPAR␣ knockout [PPAR␣(Ϫ/Ϫ)] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPAR␣ gene. Compared to wildtype mice, treatment of PPAR␣(Ϫ/Ϫ) mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPAR␣ transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPAR␣ target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPAR␣ protects against amiodarone-induced hepatotoxicity.

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Section: Resultsmentioning

confidence: 97%

Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-αTarget Gene Activation

McCarthy

Pollak²,

Hanniman³

et al. 2004

J Pharmacol Exp Ther

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“…However, the ions provide a high internal energy during the ionization process, often leading to fragmentation of the molecules. FAB is a powerful tool for the structural characterization of polar thermolabile compounds, such as a drug and its metabolites, [136][137][138][139] or natural compounds 140,141 and biomolecules. [24][25][26][27] Thermospray ionization (TSP) was developed as an LC/MS interface method by Vestal et al in 1983.…”

Section: ·3 Othersmentioning

confidence: 99%

Biomedical and Biological Mass Spectrometry

Mano

Goto

2003

ANAL. SCI.

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By the end of the 20th century, mass spectrometry (MS) had evolved drastically as a major analytical tool in biomedical and biological research. Recent mass spectrometers, designed for ease of handling, came into wide use in the 1990s. Soft ionization methods, which were made practical in the second half of the 1980s, allowed for the sensitive analysis of nonvolatile and thermolabile compounds by MS. Electrospray ionization (ESI) 1,2 and matrix-assisted laser desorption ionization (MALDI) 3 methods, made it possible to ionize large biomolecules and to transfer them to the gas phase, thereby becoming a valuable tool in both protein and peptide analysis [4][5][6] and in the study of drugs and their metabolites [7][8][9][10][11][12] in the human body. Many reviews of MS have recently been published, [13][14][15][16][17][18][19] and in particular, the number of reviews describing biochemical, biological, and biomedical MS have increased dramatically over the last ten years. Initially, there were many commentary reviews on new techniques, such as soft ionization methods and mass analyzers, 13-15 and more recently, review articles have focused on the biological and biomedical applications of MS. 18-21 Above all, two major fields, drug discovery and proteomics, have made marked advances based on MS.Articles in the MEDLINE database were searched, and the results are illustrated in Fig. 1 and Table 1. Over the last 15 years, a total of 79220 MS articles were placed in the database, with a 2.5-fold increase from 1987 to 1999. The number of articles using fast atom bombardment (FAB) as an ionization method remained almost constant during this period. This ionization method is a practical soft ionization procedure, which was applied to the analysis of peptides [22][23][24][25][26][27][28][29][30][31] and endogenous biological substances [32][33][34][35] in the 1980s. Atmospheric pressure chemical ionization (APCI) is a suitable method 36 for the ionization of middle or weakly polar low-molecular-weight molecules, and can be easily coupled to conventional highperformance liquid chromatography (HPLC), used at a flow rate of around 1 mL/min. [37][38][39][40][41][42][43][44][45][46][47][48] However, the number of articles concerning APCI have increased slowly, because most drugs developed recently contain polar groups which can be ionized without difficulty by the ESI technique. Japan This review focuses on biological and biomedical mass spectrometry, and covers a selection of publications in this area included in the MEDLINE database for the period 1987 -2001. Over the last 15 years, biological and biomedical mass spectrometry has progressed out of all recognition. The development of soft ionization methods, such as electrospray ionization and matrix-assisted laser desorption ionization, has mainly contributed to the remarkable progress, because they can easily produce gas-phase ions of large, polar, and thermally labile biomolecules, such as proteins, peptides, nucleic acids and others. The innovations of ionization meth...

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“…Biotransformation in the liver is the main pathway for AM elimination with several metabolites being formed 7–9. These products include mono‐ N ‐desethylamiodarone (DEA), di‐ N ‐desethylamiodarone and deiodinated desethylamiodarone, each of which is present in the blood and/or plasma of human and animal models 7, 9, 10. Of these, DEA is especially important due to its pharmacological and toxicological activities and the presence of high circulating plasma and tissue levels in humans, which may exceed the concentrations of the parent drug itself 3, 11–14.…”

Section: Introductionmentioning

confidence: 99%