Concentration dependent mitochondrial effect of amiodarone

Varbiro, Gabor; Tóth, Ambrus; Tapodi, Antal; Veres, Balázs; Sümegi, Balázs; Gallyas, Ferenc

doi:10.1016/s0006-2952(02)01660-x

Cited by 43 publications

(33 citation statements)

References 38 publications

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“…The observation that amiodarone protected the energy metabolism in perfused hearts suggested that the cardioprotectivity of the drug could be consequence of its direct mitochondrial effect, by influencing ⌬⌿, ROS production, respiration, or permeability transition. Although some studies addressed the effect of amiodarone and desethylamiodarone on mitochondrial respiration and ROS production (Fromenty et al, 1990;Di Matola et al, 2000), the effect of the drugs on permeability transition has not been fully disclosed (Varbiro et al, 2003), although the involvement of permeability transition in the collapse of oxidative phosphorylation and ion homeostasis, as well as in mediation of both necrotic and apoptotic cell death is well established (Kroemer and Reed, 2000). Therefore, we studied jpet.aspetjournals.org the direct effect of the drugs on isolated, Percoll-gradient purified mitochondria from rat liver and heart, as well as the effect of amiodarone on the release of AIF from mitochondria and its translocation to the nucleus in perfused rat hearts.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, there are only limited data about the effect of desethylamiodarone on ischemic heart. We have previously demonstrated that amiodarone increases the level of the high-energy phosphate metabolites by directly influencing the mitochondria after ischemia and reperfusion in perfused rat hearts (Varbiro et al, 2003). Myocardial ischemia can lead to a severe arrhythmia that may necessitate amiodarone administration; therefore, it is important to assess the effect of amiodarone and its metabolite desethylamiodarone on postischemic heart.…”

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Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Varbiro¹,

Tóth²,

Tapodi³

et al. 2003

J Pharmacol Exp Ther

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Amiodarone is a widely used and potent antiarrhythmic agent that is metabolized to desethylamiodarone. Both amiodarone and its metabolite possess antiarrhythmic effect, and both compounds can contribute to toxic side effects. Here, we compare the effect of amiodarone and desethylamiodarone on mitochondrial energy metabolism, membrane potential, and permeability transition and on mitochondria-related apoptotic events. Amiodarone but not desethylamiodarone protects the mitochondrial energy metabolism of the perfused heart during ischemia in perfused hearts. At low concentrations, amiodarone stimulated state 4 respiration due to an uncoupling effect, inhibited the Ca 2ϩ -induced mitochondrial swelling, whereas it dissipated the mitochondrial membrane potential (⌬⌿), and prevented the ischemia-reperfusion-induced release of apoptosis-inducing factor (AIF). At higher concentrations, amiodarone inhibited the mitochondrial respiration and simulated a cyclosporin A (CsA)-independent mitochondrial swelling. In contrast to these, desethylamiodarone did not stimulate state 4 respiration, did not inhibit the Ca 2ϩ -induced mitochondrial permeability transition, did not induce the collapse of ⌬⌿ in low concentrations, and did not prevent the nuclear translocation of AIF in perfused rat hearts, but it induced a CsA-independent mitochondrial swelling at higher concentration, like amiodarone. That is, desethylamiodarone lacks the protective effect of amiodarone seen at low concentrations, such as the inhibition of calcium-induced mitochondrial permeability transition and inhibition of the nuclear translocation of the proapoptotic AIF. On the other hand, both amiodarone and desethylamiodarone at higher concentration induced a CsA-independent mitochondrial swelling, resulting in apoptotic death that explains their extracardiac toxic effect.Amiodarone (2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl-ketone hydrochloride) is one of the most effective antiarrhythmic drugs and is frequently used in the clinical practice for treating ventricular and supraventricular arrhythmias. It is a class III antiarrhythmic agent, prolonging action potential duration whose effect may involve blocking of ␤-adrenergic receptors, sodium channels, and L-type calcium channels (Singh and Vaughan Williams, 1970;Nokin et al., 1983;Nattel et al., 1987;Varro et al., 1996). It may also have a role in preventing mortality after myocardial infarction (Julian et al., 1997). Despite its effective antiarrhythmical properties, the use of amiodarone is often limited by its toxic side effects, including thyroid dysfunction, liver, and pancreas fibrosis (Amico et al., 1984;Martin and Howard, 1985). However, the most severe adverse effect of the drug is pulmonary fibrosis, occurring in up to 13% of the patients receiving the amiodarone in doses higher than 400 mg day Ϫ1 (Martin and Rosenow, 1988). The etiology of the amiodarone-induced pulmonary toxicity is unknown.Desethylamiodarone, the major metabolite of amiodarone, also has antiarrhyth...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Varbiro¹,

Tóth²,

Tapodi³

et al. 2003

J Pharmacol Exp Ther

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“…The amount of water-insoluble blue M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 PARP inhibition promotes Taxol resistance via Akt activation 7 formasan dye formed from MTT + was proportional to the number of live cells, and was determined with an Anthos Labtech 2010 ELISA reader (Vienna, Austria) at 550nm wavelength after dissolving the blue formasan precipitate in 10% sodium dodecyl sulfate. All experiments were run with at least 4 replicate cultures and repeated 3 times [26,27].…”

Section: Page 5 Of 44mentioning

confidence: 99%

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

Szántó

Hellebrand

Bognár

et al. 2009

Biochemical Pharmacology

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Running Title: PARP inhibition promotes Taxol resistance via Akt activationThe nonstandard abbreviations used are: PARP, Poly (ADP-ribose) polymerase; PAR, poly (ADP-ribose); PI-3K, phosphatidylinositol-3-kinase; Akt/PKB, protein kinase B; MTT + , 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance.Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinaseAkt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.

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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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Concentration dependent mitochondrial effect of amiodarone

Cited by 43 publications

References 38 publications

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

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

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