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Ferenc Follath - One of the best experts on this subject based on the ideXlab platform.
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hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Katri Waldhauser, Karin Brecht, Michael Torok, Urs Thomet, Daniel Konrad, Ferenc Follath, Stephan KrahenbuhlAbstract:The aim of this work was to compare hepatocellular toxicity and pharmacological activity of amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran; B2-O-Et-N-diethyl) and of eight amiodarone derivatives. Three amiodarone metabolites were studied, namely, mono-N-desethylamiodarone (B2-O-Et-NH-ethyl), di-N-desethylamiodarone (B2-O-Et-NH(2)), and (2-butyl-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)-methanone (B2) carrying an ethanol side chain [(2-butylbenzofuran-3-yl)-[4-(2-hydroxyethoxy)-3,5-diiodophenyl]-methanone; B2-O-Et-OH]. In addition, five amiodarone analogs were investigated, namely, N-dimethylamiodarone (B2-O-Et-N-dimethyl), N-dipropylamiodarone (B2-O-Et-N-dipropyl), B2-O-carrying an acetate side chain [[4-(2-butyl-benzofuran-3-carbonyl)-2,6-diiodophenyl]-acetic acid; B2-O-acetate], B2-O-Et carrying an propionamide side chain (B2-O-Et-propionamide), and B2-O carrying an ethyl side chain [(2-butylbenzofuran-3-yl)-(4-ethoxy-3,5-diiodophenyl)-methanone; B2-O-Et]. A concentration-dependent increase in lactate dehydrogenase leakage from HepG2 cells and isolated rat hepatocytes was observed in the presence of amiodarone and of most analogs, confirming their hepatocellular toxicity. Using freshly isolated rat liver mitochondria, amiodarone and most analogs showed a dose-dependent toxicity on the respiratory chain and on beta-oxidation, significantly reducing the respiratory control ratio and oxidation of palmitate, respectively. The reactive oxygen species concentration in hepatocytes increased time-dependently, and apoptotic/necrotic cell populations were identified using flow cytometry and annexin V/propidium iodide staining. The effect of the three least toxic amiodarone analogs on the human ether-a-go-go-related gene (hERG) channel was compared with amiodarone. Amiodarone, B2-O-acetate, and B2-O-Et-N-dipropyl (each 10 microM) significantly reduced the hERG tail current amplitude, whereas 10 microM B2-O-Et displayed no detectable effect on hERG outward potassium currents. In conclusion, three amiodarone analogs (B2-O-Et-N-dipropyl, B2-O-acetate, and B2-O-Et) showed a lower hepatocellular toxicity profile than amiodarone, and two of these analogs (B2-O-Et-N-dipropyl and B2-O-acetate) retained hERG channel interaction capacity, suggesting that amiodarone analogs with class III antiarrhythmic activity and lower hepatic toxicity could be developed.
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the utility of serum drug level monitoring during therapy with class iii antiarrhythmic agents
Journal of Cardiovascular Pharmacology, 1992Co-Authors: Ferenc FollathAbstract:Serum drug level monitoring facilitates dosage optimization of agents with a narrow therapeutic index. Concentration-dependent antiarrhythmic and toxic effects have been demonstrated for several class I drugs, whereas the concentration-effect relationihips of class III antinrrhythmics are less well established. The efficacy and toxicity of amiodarone, in particular, may be determined more by extensive tissue deposition than by its serum concentration. Furthermore, accumulation of the active metabolite desethylamiodarone seems to play an additional role
Tsuyoshi Yokoi - One of the best experts on this subject based on the ideXlab platform.
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establishment of a mouse model for amiodarone induced liver injury and analyses of its hepatotoxic mechanism
Journal of Applied Toxicology, 2016Co-Authors: Shohei Takai, Miki Nakajima, Tsuyoshi Yokoi, Shingo Oda, Koichi Tsuneyama, Tatsuki FukamiAbstract:Drug-induced liver injury (DILI) is the most frequent cause of post-marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD-induced liver injury, mice were administered AMD [1000 mg kg–1, per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg–1, intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX-pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD-administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD-administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl3), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD-induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD-induced liver injury using an in vivo mouse model. Copyright © 2015 John Wiley & Sons, Ltd.
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inhibitory effects of amiodarone and its n deethylated metabolite on human cytochrome p450 activities prediction of in vivo drug interactions
British Journal of Clinical Pharmacology, 2000Co-Authors: Katsuhiro Ohyama, Hiroshi Yamazaki, Miki Nakajima, Noriaki Shimada, M Suzuki, Tsuyoshi YokoiAbstract:Aims To predict the drug interactions of amiodarone and other drugs, the inhibitory effects and inactivation potential for human cytochrome P450 (CYP) enzymes by amiodarone and its N-dealkylated metabolite, desethylamiodarone were examined. Methods The inhibition or inactivation potency of amiodarone and desethylamiodarone for human CYP activities were investigated using microsomes from B-lymphoblastoid cell lines expressing CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The in vivo drug interactions of amiodarone and desethylamiodarone were predicted in vitro using the 1+Iu/Ki values. Results Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4-mediated activities with Ki values of 45.1–271.6 μm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 (Ki=4.5 μm ) and noncompetitively inhibited CYP2A6 (Ki=13.5 μm ), CYP2B6 (Ki=5.4 μm ), and CYP3A4 (Ki=12.1 μm ). The catalytic activities of CYP1A1 (Ki=1.5 μm, α=5.7), CYP1A2 (Ki=18.8 μm, α=2.6), CYP2C9 (Ki=2.3 μm, α=5.9), and CYP2C19 (Ki=15.7 μm, α=4.5) were inhibited by desethylamiodarone with mixed type. The 1+Iu/Ki values of desethylamiodarone were higher than those of amiodarone. Amiodarone inactivated CYP3A4, while desethylamiodarone inactivated CYP1A1, CYP1A2, CYP2B6, and CYP2D6. Conclusions The interactions between amiodarone and other drugs might occur via the inhibition of CYP activities by its N-dealkylated metabolite, desethylamiodarone, rather than by amiodarone itself. In addition, the inactivation of CYPs by desethylamiodarone as well as by amiodarone would also contribute to the drug interactions.
Wilmar M Wiersinga - One of the best experts on this subject based on the ideXlab platform.
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dronerarone acts as a selective inhibitor of 3 5 3 triiodothyronine binding to thyroid hormone receptor α1 in vitro and in vivo evidence
Endocrinology, 2003Co-Authors: H C Van Beeren, Willeke M C Jong, Ellen Kaptein, Theo J Visser, O Bakker, Wilmar M WiersingaAbstract:Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor α1 (TRα1) and TRβ1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TRα1 and TRβ1 in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro, Dron had a inhibitory effect of 14% on the binding of T3 to TRα1, but not on TRβ1. Desethylamiodarone inhibited T3 binding to TRα1 and TRβ1 equally. Debutyldronedarone inhibited T3 binding to TRα1 by 77%, but to TRβ1 by only 25%. In vivo, AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRβ1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in...
Knut Kleesiek - One of the best experts on this subject based on the ideXlab platform.
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simultaneous measurement of amiodarone and desethylamiodarone in human plasma and serum by stable isotope dilution liquid chromatography tandem mass spectrometry assay
Journal of Pharmaceutical and Biomedical Analysis, 2010Co-Authors: Joachim Kuhn, Christian Gotting, Knut KleesiekAbstract:A stable isotope dilution liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) assay to measure amiodarone, the most frequently used agent for maintaining sinus rhythm in patients with atrial fibrillation, and its major metabolite desethylamiodarone in human plasma and serum was developed. Measurement of amiodarone and desethylamiodarone was performed during a 4.0-min run-time using amiodarone-D(4) and desethylamiodarone-D(4) as internal standards. Calibration curves covering 12 calibrators measured in four replicates each for the analysis of both amiodarone and desethylamiodarone were linear and reproducible in the range of 0.01-40.0 mg/L (r>0.999). Limits of detection in plasma matrix were 2.7 microg/L for amiodarone and 1.9 microg/L for desethylamiodarone, and lower limits of quantification in plasma matrix were 7.5 microg/L for amiodarone and 2.5 microg/L for desethylamiodarone. Interassay imprecision and inaccuracy were <8% and <9% for both substances. Mean extraction yield was 99.6% (range 92.6-107.7%) for amiodarone and 90.2% (range 80.0-94.7%) for desethylamiodarone. Agreement was moderate for amiodarone (n=162) and desethylamiodarone (n=117), respectively, between the present method and a HPLC method with UV detection using a commercially available reagent set for the HPLC analysis of these drugs. The Passing-Bablok regression line was HPLC=0.98 (LC-MS/MS)+0.10 [mg/L]; r=0.94 for amiodarone and HPLC=1.05 (LC-MS/MS)+0.02 [mg/L]; r=0.90 for desethylamiodarone. This sensitive and interference-free LC-MS/MS assay permits rapid and accurate determination of amiodarone and desethylamiodarone in human plasma and other body fluids.
H C Van Beeren - One of the best experts on this subject based on the ideXlab platform.
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dronerarone acts as a selective inhibitor of 3 5 3 triiodothyronine binding to thyroid hormone receptor α1 in vitro and in vivo evidence
Endocrinology, 2003Co-Authors: H C Van Beeren, Willeke M C Jong, Ellen Kaptein, Theo J Visser, O Bakker, Wilmar M WiersingaAbstract:Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor α1 (TRα1) and TRβ1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TRα1 and TRβ1 in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro, Dron had a inhibitory effect of 14% on the binding of T3 to TRα1, but not on TRβ1. Desethylamiodarone inhibited T3 binding to TRα1 and TRβ1 equally. Debutyldronedarone inhibited T3 binding to TRα1 by 77%, but to TRβ1 by only 25%. In vivo, AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRβ1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in...
