Physiologically based pharmacokinetic modeling to predict drug-drug interactions involving inhibitory metabolite: a case study of amiodarone.

Evaluation of drug-drug interaction (DDI) involving circulating inhibitory metabolites of perpetrator drugs has recently drawn more attention from regulatory agencies and pharmaceutical companies. Here, using amiodarone (AMIO) as an example, we demonstrate the use of physiologically based pharmacokinetic (PBPK) modeling to assess how a potential inhibitory metabolite can contribute to clinically significant DDIs. Amiodarone was reported to increase the exposure of simvastatin, dextromethorphan, and warfarin by 1.2- to 2-fold, which was not expected based on its weak inhibition observed in vitro. The major circulating metabolite, mono-desethyl-amiodarone (MDEA), was later identified to have a more potent inhibitory effect. Using a combined "bottom-up" and "top-down" approach, a PBPK model was built to successfully simulate the pharmacokinetic profile of AMIO and MDEA, particularly their accumulation in plasma and liver after a long-term treatment. The clinical AMIO DDIs were predicted using the verified PBPK model with incorporation of cytochrome P450 inhibition from both AMIO and MDEA. The closest prediction was obtained for CYP3A (simvastatin) DDI when the competitive inhibition from both AMIO and MDEA was considered, for CYP2D6 (dextromethorphan) DDI when the competitive inhibition from AMIO and the competitive plus time-dependent inhibition from MDEA were incorporated, and for CYP2C9 (warfarin) DDI when the competitive plus time-dependent inhibition from AMIO and the competitive inhibition from MDEA were considered. The PBPK model with the ability to simulate DDI by considering dynamic change and accumulation of inhibitor (parent and metabolite) concentration in plasma and liver provides advantages in understanding the possible mechanism of clinical DDIs involving inhibitory metabolites.

Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs.

STUDY OBJECTIVE: Our objective is to investigate to what extent amiodarone is sequestered by intravenously administered lipid emulsion in plasma of pigs and whether the lipid emulsion inhibits amiodarone-induced hypotension. METHODS: Twenty anesthetized pigs received randomly 1.5 mL/kg bolus injection of olive/soybean oil-based 20% lipid emulsion (lipid group, n=10) or Ringer's acetate solution (control group, n=10) in 1 minute, followed by a continuous infusion of either solution for 30 minutes at 0.25 mL/kg per minute. Simultaneously with these continuous infusions, amiodarone hydrochloride was infused for 20 minutes at 1 mg/kg per minute in both groups. Plasma amiodarone concentration and mean arterial blood pressure were evaluated at predetermined intervals. RESULTS: Plasma amiodarone concentration in the lipid group increased more steeply during the amiodarone infusion than in the control group, at 20 minutes being a median 96.8 mg/L (interquartile range [IQR] 85.4, 102.0 mg/L) in the lipid group and median 21.5 mg/L (IQR 18.9, 22.3 mg/L) in the control group (difference 75.3 mg/L; 95% confidence interval [CI] 65.3 to 85.3 mg/L). After the separation of lipids from plasma by differential centrifugation, less amiodarone was contained in the lipid-poor aqueous fraction. At 20 minutes, the median was 13.3 mg/L (IQR 12.0, 13.7 mg/L), and the difference compared with the total plasma amiodarone concentration was -83.6 mg/L (95% CI -93.3 to -73.8 mg/L). In the lipid group, mean arterial blood pressure was not altered during the continuous amiodarone infusion. In the control group, mean arterial blood pressure decreased from baseline at 11 minutes, and the median was 52 mm Hg (IQR 51, 80 mm Hg) and the difference from baseline was 26 mm Hg (95% CI 9 to 43 mm Hg). Mean arterial blood pressure at 21 minutes also remained below the baseline, and the median was 57 mm Hg (IQR 50, 68 mm Hg) and the difference from baseline was 21 mm Hg (95% CI 9 to 33 mm Hg). CONCLUSION: Amiodarone was sequestered to a great extent by the intravenously administered lipids in plasma, which completely prevented the decrease in arterial blood pressure caused by amiodarone infusion. Further studies are needed to evaluate the clinical usefulness of intravenous lipid emulsion as an antidote in amiodarone overdoses.

Effects of tomato extract on oxidative stress induced toxicity in different organs of rats.

Tomato products containing lycopene are believed to be associated with decreased risk of chronic diseases including cancer, and its effects are suggested to be due to antioxidant effect of lycopene. The aim of this research was to study the effects of tomato extract on acetaminophen (APAP), amiodarone (ADN) and cyclosporine A (CsA)-induced liver, lung and kidney toxicity, respectively. Previous studies have shown that free radical reactions may play important roles in toxicity of these drugs. Rats received a single dose of APAP (750mg/kg, i.p.) before treatment with tomato extract (5mg/kg, oral) for seven consecutive days, ADN (100mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 10 consecutive days, or CsA (250mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 14 consecutive days. At the end of each treatment, the animals were sacrificed and the related organ tissues were collected for biochemical and histopathological examinations. Simultaneous treatment of tomato extract ameliorated tissue damage, biochemical indices, and oxidative stress parameters against APAP-induced acute hepatotoxicity, but had less beneficial effects on ADN-induced lung toxicity and little effect against CsA-induced nephrotoxicity. Therefore, tomato products may be beneficial for the prevention and therapy of toxicity induced by ADN and APAP.

Direct mitochondrial dysfunction precedes reactive oxygen species production in amiodarone-induced toxicity in human peripheral lung epithelial HPL1A cells.

Amiodarone (AM), a drug used in the treatment of cardiac dysrrhythmias, can produce severe pulmonary adverse effects, including fibrosis. Although the pathogenesis of AM-induced pulmonary toxicity (AIPT) is not clearly understood, several hypotheses have been advanced, including increased inflammatory mediator release, mitochondrial dysfunction, and free-radical formation. The hypothesis that AM induces formation of reactive oxygen species (ROS) was tested in an in vitro model relevant for AIPT. Human peripheral lung epithelial HPL1A cells, as surrogates for target cells in AIPT, were susceptible to the toxicity of AM and N-desethylamiodarone (DEA), a major AM metabolite. Longer incubations (> or =6 h) of HPL1A cells with 100 microM AM significantly increased ROS formation. In contrast, shorter incubations (2 h) of HPL1A cells with AM resulted in mitochondrial dysfunction and cytoplasmic cytochrome c translocation. Preexposure of HPL1A cells to ubiquinone and alpha-tocopherol was more effective than that with Trolox C or 5,5-dimethylpyrolidine N-oxide (DMPO) at preventing AM cytotoxicity. These data suggest that mitochondrial dysfunction, rather than ROS overproduction, represents an early event in AM-induced toxicity in peripheral lung epithelial cells that may be relevant for triggering AIPT, and antioxidants that target mitochondria may potentially have beneficial effects in AIPT.

Silymarin and vitamin E reduce amiodarone-induced lysosomal phospholipidosis in rats.

Several antioxidants have been shown to reduce lysosomal phospholipidosis, which is a potential mechanism of amiodarone toxicity, and prevent amiodarone toxicity by antioxidant and/or non-antioxidant mechanisms. The aim of this study was to test whether the co-administration of two structurally different antioxidants vitamin E and silymarin with amiodarone can reduce amiodarone-induced lysosomal phospholipidosis, and if yes, by reducing the tissue concentration of amiodarone and desethylamiodarone or by their antioxidant action. To this end, male Fischer 344 rats were treated by gavage once a day for 3 weeks and randomly assigned to the following four experimental groups: 1, control; 2, amiodarone (150 mg/(kg per day)); 3, amiodarone (150 mg/(kg per day)) plus vitamin E (100 mg/(kg per day)); 4, amiodarone (150 mg/(kg per day)) plus silymarin (60 mg/(kg per day)) treated groups. Total plasma phospholipid (PL), liver-conjugated diene, thiobarbituric acid reactive substances (TBARSs), amiodarone and desethylamiodarone concentrations were determined and the extent of lysosomal phospholipidosis in the liver was estimated by a semi-quantitative electron microscopic method. Amiodarone treatment increased significantly the liver-conjugated diene (P<0.001), TBARS (P=0.012), plasma total PL (P<0.001) concentrations compared with control. Antioxidants combined with amiodarone significantly decreased the liver-conjugated diene (P<0.001 for both), TBARS (P=0.016 for vitamin E, P=0.053 borderline for silymarin) and plasma total PL (P=0.058 borderline for vitamin E, P<0.01 for silymarin) concentrations compared with amiodarone treatment alone. Silymarin significantly (P=0.021) reduced liver amiodarone, but only tended to decrease desethylamiodarone concentration; however, vitamin E failed to do so. Amiodarone treatment increased lysosomal phospholipidosis (P<0.001) estimated by semi-quantitative electron microscopic method and both antioxidants combined with amiodarone reduced significantly (P<0.001 for both) the amiodarone-induced lysosomal phospholipidosis. In conclusion, silymarin presumably reduced lysosomal phospholipidosis by both antioxidant action and its liver amiodarone concentration decreasing effect, while vitamin E exerted similar effect by antioxidant action alone. Thus, both antioxidant action and inhibition of tissue uptake of amiodarone might have an important role in the preventative effect of antioxidants against amiodarone toxicity.

Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction.

Amiodarone (AM) is an efficacious antidysrhythmic agent that can cause numerous adverse effects, including potentially life-threatening pulmonary fibrosis. The current study was undertaken to investigate potential protective mechanisms of vitamin E against AM-induced pulmonary toxicity (AIPT) in the hamster. Three weeks after intratracheal administration of AM (1.83 micromol), increased pulmonary hydroxyproline content and histological damage were observed, indicative of fibrosis. These effects were preceded by increased pulmonary levels of transforming growth factor (TGF)-beta1 mRNA at 1 week post-AM, which remained elevated 3 weeks post-AM. Dietary supplementation with vitamin E resulted in rapid pulmonary accumulation of the vitamin, and prevention of AM-induced increases in TGF-beta1, hydroxyproline, and histological damage. Although dietary supplementation also markedly elevated lung mitochondrial vitamin E content, it did not attenuate AM-induced inhibition of mitochondrial respiration or disruption of mitochondrial membrane potential in vitro, or lung mitochondrial respiratory inhibition resulting from in vivo AM administration. These results suggest that vitamin E reduces the extent of pulmonary damage after AM administration via down-regulating TGF-beta1 overexpression but that it does not modify AM-induced mitochondrial dysfunction, a potential initiating event in AIPT.

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level.

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

Desethylamiodarone prolongation of cardiac repolarization is dependent on gene expression: a novel antiarrhythmic mechanism.

Desethylamiodarone (DEA) is the major metabolite of amiodarone and has similar electrophysiologic effects with prolongation of the repolarization that is reversed by thyroid hormone (T3). Some of the electrophysiologic effects are probably due to antagonism of T3 at the receptor level. Such effects of T3 are mediated by modulation of gene transcription. The aim of this study was to investigate whether cycloheximide (Cy), an inhibitor of protein synthesis, and actinomycin D (ActD), a RNA-synthesis inhibitor, block DEA-induced prolongation of the repolarization and whether DEA takes part in the autoregulation of the nuclear thyroid hormone-receptor subtypes (ThR). Corrected monophasic action potentials (MAPc) and QTc were measured in Langendorff-perfused guinea pig hearts for 1 h. The hearts were continuously perfused with (a) vehicle, (b) 7.5 microM Cy, (c) 5 microM DEA, (d) 5 microM DEA + 7.5 microM Cy, (e) 1 microM T3, (f) 5 microM DEA + 1 microM T3, (g) 1.5 microM ActD, and (h) ActD + DEA. A potassium channel blocker with class III antiarrhythmic effects, 0.5 microM almokalant, was used as a control, separately and together with Cy. Western blot analysis for the ThR subtypes alpha, beta1, and beta2 was performed on vehicle- and DEA-treated hearts. DEA increased MAPc by 19% (p < 0.0005) and QTc by 18% (p < 0.0005). There was no effect on MAPc or QTc when Cy, ActD, or T3 was added with DEA. Almokalant increased MAPc by 14% (p < 0.005) and QTc by 13% (p < 0.0005). When Cy was present, almokalant still induced a similar prolongation of MAPc by 14% (p < 0.005) and QTc by 17% (p < 0.0005). Western blot analysis revealed no change in the expression of the ThR protein. In conclusion, the prolongation of the cardiac repolarization by DEA, but not almokalant, can be totally blocked by Cy and ActD. This indicates that the class III action of DEA is at least in part dependent on transcription rather than a direct effect on cell-membrane channels or receptors. The action of DEA could be reversed by T3, indicating an antagonism between DEA and T3. These results suggest a new antiarrhythmic mechanism dependent on gene expression.

Toxicity of amiodarone on mouse pulmonary endothelial cells cultured with or without alveolar macrophages.

This study was designed to specify the toxicity of amiodarone toward mouse pulmonary endothelial cells in comparison with that of another cationic amphiphilic drug, i.e., mianserin. These examinations were performed in the absence and presence of mouse alveolar macrophages under transmembrane co-culture or in direct contact with the endothelial cells to assess the contribution of macrophages to the toxicities toward the endothelial cells. As a result of 24-hr treatment, amiodarone caused a decrease in cell viability, in H(+)-ATPase, acid sphingomyelinase, and acid phospholipase A2 activities, and in neutral red uptake, and an increase in permeability of the endothelial cells. Because the magnitude of changes in the endothelial cells was the greatest under direct contact with macrophages, and was the mildest without macrophages, macrophages were considered to enhance the toxicity of amiodarone toward the endothelial cells. Additionally, the toxic effect of amiodarone on the cells was depressed by pretreatment of them with docosahexaenoic acid (DHA) or alpha-tocopherol for 2 days and co-treatment with these agents for 1 day, but not with prednisolone or indomethacin co-treatment. DHA and alpha-tocopherol protected endothelial cells from the toxicity of amiodarone. The effect was more potent for DHA than alpha-tocopherol.

Nongoitrous (type I) amiodarone-associated thyrotoxicosis: evidence of follicular disruption in vitro and in vivo.

Treatment with the antiarrhythmic agent amiodarone results in alterations in thyroid hormone metabolism, and can induce either hypothyroidism or hyperthyroidism (amiodarone-associated thyrotoxicosis, AAT). AAT occurs in patients both with and without preexisting goiter. In our study of the nongoitrous variety, the effect in vitro of amiodarone treatment and of concurrent treatment with potential inhibitors on thyroid cells (FRTL-5) was assessed by measuring the release of radiolabeled chromium (51Cr). In addition, thyroid histopathology was evaluated in autopsy specimens from six amiodarone-treated patients who had no pretreatment evidence of thyroid disease. Histopathologic examination revealed minimal or no evidence of thyroid follicular damage in specimens from amiodarone-treated euthyroid patients (n = 4). In contrast, moderate to severe follicular damage and disruption were present in glands from patients with AAT (n = 2). Studies in vitro showed amiodarone to be cytotoxic to thyroid cells; this effect was inhibited by treatment with dexamethasone (10(-3) mmol) or perchlorate (2.5 micrograms/mL). In summary, we demonstrate evidence in vitro and in vivo of amiodarone-induced thyroid follicular damage and disruption in specimens from patients with nongoitrous AAT and in cultured normal thyroid cells. In addition, we demonstrate inhibition of this effect following treatment in vitro with dexamethasone or perchlorate. Our findings support the concept that nongoitrous (type I) AAT results from direct drug toxicity with disruption of thyroid follicles and subsequent release of preformed thyroid hormone.

Antagonism between T3 and amiodarone on the contractility and the density of beta-adrenoceptors of chicken cardiac myocytes.

3,3',5-Triiodothyronine (T3), at 10(-8) M, potentiated by 26.4-30.9% the isoproterenol-mediated inotropic effect in chick embryo cardiac myocytes in culture. Amiodarone (10(-6) M) decreased this response by 44.6% only in cells cultured with serum, where the T3 concentration was 10(-13) M. Amiodarone inhibited the potentiating effect of T3. Amiodarone alone had no influence on the beta-adrenoceptor density in cells cultured in serum-free medium. This confirms that the effects of amiodarone on cardiac beta-adrenoceptors are T3 dependent. T3 increased the density of beta-adrenoceptors through two concentration ranges, with an initial 30% increase between 10(-14) and 10(-11) M, followed by a second increase until 10(-7) M. Amiodarone not only inhibited the first positive effect of T3 but also decreased beta-adrenoceptor density far below the control value. The second positive T3 effect was also inhibited by 50% by amiodarone. This study suggests that T3 might increase the number of cell-surface beta-adrenoceptors and modify their cellular traffic through at least two mechanisms, one assumed to be non-genomic, the other being genomic, and that amiodarone could affect the two mechanisms differently.

Isoproterenol antagonizes drug-induced prolongation of action potential duration in humans.

The effects of an isoproterenol infusion on the duration of the human right ventricular endocardial monophasic action potential at 90% repolarization were recorded in the absence and in the presence of an antiarrhythmic drug regimen containing class III effects in two similar groups of patients. The drugs used were amiodarone (N = 3, 300 +/- 50 mg), sotalol plus quinidine (N = 11, 156 +/- 13 mg sotalol, 1688 +/- 594 mg quinidine), and sotalol alone (N = 3, 300 +/- 20 mg). All patients had underlying coronary disease but no evidence of inducible ischemia. In the absence of antiarrhythmic drug, isoproterenol did not significantly change the relationship of action potential duration at 90% repolarization to cycle length; there was a linear decrease in action potential duration by 19.8% between a paced cycle length of 600 and 300 ms. Isoproterenol did not significantly shorten the action potential duration at any cycle length. However, isoproterenol decreased the ventricular effective refractory period at 400 ms drive from 240 +/- 5.0 to 225 +/- 6.0 ms (p < 0.05) accompanied by no change in the ratio of refractory period to steady-state action potential duration. In the presence of class III drug effects, the action potential duration was increased by an average of 9.2% at all paced cycle lengths longer than 300 ms (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal QT intervals associated with negative T waves induced by antiarrhythmic drugs are rapidly reduced using magnesium sulfate as an antidote.

This study was undertaken to determine whether prolonged QTc interval as a consequence of abnormal repolarization induced by coronary disease or antiarrhythmic drugs could be shortened by intravenous administration of magnesium sulfate. A total of 21 patients with basal prolonged QTc intervals (QTc > 500 ms) were divided in two groups: 7 with ischemic coronary disease and negative T waves (Group A), and 14 treated with antiarrhythmic drugs (Group B). Nine of the latter had negative T waves (Subgroup B-1) and five had positive T waves (Subgroup B-2) recorded in precordial leads. Nine patients were taking amiodarone and six quinidine. Magnesium sulfate was given intravenously in a bolus of 3.75 g (25% solution) over 3 min. Patients had normal electrolyte serum levels. The prolonged QTc and JTc intervals were shortened after magnesium sulfate in patients of Subgroup B-1 from the basal values [QTc 20.7% and JTc 25.4%, (p = < 0.0001 and 0.02, respectively)]. None of the patients in Group A or Subgroup B-2 experienced altered QTc or JTc intervals. While some antiarrhythmic drugs are capable of altering the refractoriness of ventricular cells, probably by causing changes in the intracellular metabolic pathways, in patients with coronary disease gaps in the membrane induced by ischemic injury let calcium enter the cells parallel with dispersion of ventricular repolarization. When secondary negative T waves are present, magnesium sulfate as an antidote probably acts as a blocking agent at the sarcoplasmic reticulum, thus reducing both QTc and JTc intervals.

Attenuation of amiodarone-induced lung fibrosis and phospholipidosis in hamsters by taurine and/or niacin treatment.

Therapeutic use of amiodarone (AD), an effective antiarrhythmic drug, is associated with serious pulmonary toxicity (e.g., fibrosis and phospholipidosis). In the present study, we tested if taurine and/or niacin, which prevent bleomycin-induced lung toxicity, could prevent AD-induced lung toxicity in hamsters. AD alone significantly increased lung hydroxyproline (an index of fibrosis) and lung phospholipid (an index of phospholipidosis) levels to 154 and 133% of their control counterparts at 21 days, respectively. However, treatment of hamsters with taurine, niacin or taurine + niacin for 6 days before AD, and daily thereafter, significantly decreased subsequent AD-induced collagen accumulation. Similarly, phospholipid levels in niacin + AD and taurine + niacin + AD groups were decreased significantly compared to AD alone. We conclude that taurine and niacin administered p.o. either singly or in combination can significantly decrease AD-induced increases in lung collagen deposition and phospholipidosis and may, therefore, be potentially useful in reducing AD-induced pulmonary toxicity.

Reversal of antiarrhythmic drug effects by epinephrine: quinidine versus amiodarone.

Although previous studies have demonstrated that the electrophysiologic effects of many antiarrhythmic agents can be reversed by catecholamines, the susceptibility of amiodarone to such reversal is unknown. The objective of this study was to compare the relative degree of reversal of the electrophysiologic effects of quinidine and amiodarone by epinephrine infusions that result in plasma epinephrine levels similar to those achieved during various physiologic stresses. Twenty-nine patients who had inducible sustained monomorphic ventricular tachycardia and underwent electropharmacologic testing with quinidine and amiodarone were enrolled in the study. The variables measured before and during an epinephrine infusion (25 or 50 ng/kg per min) included the sinus cycle length, mean arterial pressure, QT interval and effective refractory period at drive train cycle lengths of 600 and 400 ms. The effective refractory period measured at a drive train cycle length of 600 ms shortened less during amiodarone therapy (2 +/- 2%) than during quinidine therapy (6 +/- 4%) or than in the baseline state (6 +/- 4%; p less than 0.01). Similar results were obtained during evaluation of the effective refractory period at a cycle length of 400 ms. Epinephrine infusion, at both 25 and 50 ng/kg per min, completely reversed the effects of quinidine and partially reversed the effects of amiodarone on the effective refractory period. The effects of epinephrine on the sinus cycle length and QT interval were similar in the baseline state and in conjunction with quinidine and amiodarone. Twenty-four patients underwent programmed ventricular stimulation during amiodarone therapy alone and in conjunction with either a 25- or a 50-ng/kg per min infusion of epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

[Possibilities of antioxidant therapy in the prevention of side effects of amiodarone]. / Az antioxidáns therapia lehetöségei az amiodaron mellékhatások megelözésében, illetve kivédésében.

The authors demonstrated the generation of a very reactive phenyl radical from amiodarone in a reducing molecular environment by pulse radiolysis study. The various antioxidants are probably not capable of preventing the generation of phenyl radical, as well as to protect against its damaging effects on the neighboring molecules. Electron microscopic studies from lung tissue of in vivo treated rats showed that the simultaneous Silibinin (a flavonoid type antioxidant) treatment with amiodarone decreased significantly the lysosomal phospholipoidosis induced by amiodarone compared with the amiodarone treated group, but it didn't prevent entirely the accumulation of lysosomal phospholipids. The in vitro lysosomal beta-glucuronidase enzyme release measured from the liver tissue of in vivo treated rats increased significantly on amiodarone treatment, the antioxidants used (Silibinin, and the dihydroquinoline type MTDQ-DA) didn't exert any favorable effect. The authors discuss in details the possible relationships between free radical reactions and lysosomal phospholipoidosis.

Amiodarone-induced injury of human pulmonary artery endothelial cells: protection by alpha-tocopherol.

Amiodarone is a potent antidysrhythmic drug that is associated with severe pulmonary toxicity. The mechanism of amiodarone pulmonary toxicity is poorly understood. To investigate the possible involvement of oxygen-derived metabolites in amiodarone-induced injury, 51Cr-labeled human pulmonary artery endothelial (HPAE) cells were incubated with amiodarone for 18 hr in the presence of various antioxidants and in hypoxic and hyperoxic conditions with cell injury quantified by 51Cr release, expressed as cytotoxic index. Amiodarone (10-50 microM) directly injured HPAE cells in a concentration-dependent manner, but the injury was not modulated by altering ambient oxygen concentrations. Furthermore, amiodarone-induced injury (30 microM) was not reduced by the following antioxidants: catalase, superoxide dismutase, ascorbic acid, dimethyl sulfoxide and ethanol. In contrast, toxicity from 30 microM amiodarone was significantly reduced by alpha-tocopherol (alpha-TOC) at 10, 20 and 40 microM from a cytotoxic index of 41.6 +/- 3.5 to 25.5 +/- 7.9, 10.61 +/- 5.4 and 3.1 +/- 2.8, respectively. As revealed by phase microscopy, alpha-TOC (40 microM) prevented any evidence of toxicity to the amiodarone-treated cells. Amiodarone concentrations in the HPAE cells incubated in the presence and absence of alpha-TOC were not significantly different, indicating that alpha-TOC did not interfere with the uptake of the drug by the cells. Similarly, amiodarone did not interfere with the uptake of alpha-TOC by the HPAE cells. Although the specific mechanism of action remains unclear, alpha-TOC affords nearly complete protection in vitro from the cellular injury induced by amiodarone.