Amiodarone-Induced Liver Toxicity

Morse, R.; Valenzuela, Gregg A.; Greenwald, T P; Eulie, P J; Wesley, Robert C.; McCallum, R

doi:10.7326/0003-4819-109-10-838

Cited by 32 publications

(15 citation statements)

References 6 publications

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“…Experiments were performed as previously described 22 with the modifications described by Spaniol et al 5 Ketone body formation by liver mitochondria was measured in the presence of an acetyl-CoA-generating system using freeze-thawed mitochondria according to Chapman et al 23 with the modifications described by Spaniol et al 5 The supernatants of the incubations were analyzed for acetoacetate according to Olsen 24 , using an enzyme-catalyzed reaction inducing changes in the concentration of ␤-nicotinamide adenine dinucleotide.…”

Section: Oxygen Uptakementioning

confidence: 99%

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

et al. 2005

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Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 mol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 mol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [mol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial ␤-oxidation was decreased by 71%, 87%, and 58% with 100 mol/L amiodarone or benzarone and 50 mol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and ␤-oxidation only at 100 mol/L. In the presence of 100 mol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.

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Section: Oxygen Uptakementioning

confidence: 99%

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

et al. 2005

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“…As is the case for most drugs, the adverse effects can limit its clinical utility. Chronic administration of AM is associated with a wide range of toxic side effects in a variety of tissues including liver [4], lung [5], thyroid [6] and pancreas [7]. Plasma concentration monitoring for AM can be a useful adjunct in clinical practice, as a narrow therapeutic range for the drug has been proposed (0.5-2.0 mg/l in plasma) [8].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Shayeganpour

Hamdy

Brocks

2008

Biopharm & Drug Disp

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The pharmacokinetics of desethylamiodarone (DEA), the active metabolite of amiodarone (AM), were studied in the rat after administration of AM or preformed metabolite. Rats received 10 mg/kg of either intravenous or oral AM HCl or DEA base. Blood samples were obtained via a surgically implanted jugular vein cannula. Plasma concentrations were measured by a validated LC/MS method. In all AM treated rats, AM plasma concentrations greatly exceeded those of the formed DEA. The fraction of AM converted to DEA after i.v. administration was 14%. Amiodarone had a significantly lower (approximately 50%) clearance than DEA, although the volume of distribution and terminal phase half-life did not differ significantly. The hepatic extraction ratio of DEA was 0.48, similar to that of AM (0.51). Oral AM demonstrated higher plasma AUC (5.6 fold) and higher C(max) (6.1 fold) than oral DEA and oral bioavailability of AM (46%) was greater than DEA (17%). The estimated fraction of the oral dose of AM converted to DEA was 4.5 fold higher than after i.v. administration, suggesting first-pass formation of DEA from AM. Amiodarone and DEA differed in their pharmacokinetic characteristics mostly due to a higher CL of DEA. With oral dosing, AM appeared to undergo significant presystemic first-pass metabolism within the intestinal tract.

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“…In addition, it has an inhibitory effect on fast sodium as well as on calcium channels (Singh, 1996). Similar to its pharmacological action, amiodarone's adverse reaction profile is complex, ranging from thyroidal (Harjai and Licata, 1997) to pulmonary (Jessurun et al, 1998), ocular (Pollak, 1999), and/or liver toxicity (Morse et al, 1988;Lewis et al, 1989). Amiodarone is a mitochondrial toxicant, uncoupling oxidative phosphorylation and inhibiting the electron transport chain and ␤-oxidation of fatty acids (Fromenty et al, 1990a,b;Spaniol et al, 2001a;Kaufmann et al, 2005).…”

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confidence: 99%

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

Waldhauser

Török

et al. 2006

J Pharmacol Exp Ther

105

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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-Ndiethyl) and of eight amiodarone derivatives. Three amiodarone metabolites were studied, namely, mono-N-desethylamioda- 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 ␤-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 M) significantly reduced the hERG tail current amplitude, whereas 10 M 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-Ndipropyl 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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Amiodarone-Induced Liver Toxicity

Cited by 32 publications

References 6 publications

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

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