Metabolite Desethylamiodarone Research Articles

Comparison of Mitochondrial and Antineoplastic Effects of Amiodarone and Desethylamiodarone in MDA-MB-231 Cancer Line.

Previously, we have demonstrated that amiodarone (AM), a widely used antiarrhythmic drug, and its major metabolite desethylamiodarone (DEA) both affect several mitochondrial processes in isolated heart and liver mitochondria. Also, we have established DEA's antitumor properties in various cancer cell lines and in a rodent metastasis model. In the present study, we compared AM's and DEA's mitochondrial and antineoplastic effects in a human triple-negative breast cancer (TNBC) cell line. Both compounds reduced viability in monolayer and sphere cultures and the invasive growth of the MDA-MB-231 TNBC line by inducing apoptosis. They lowered mitochondrial trans-membrane potential, increased Ca2+ influx, induced mitochondrial permeability transition, and promoted mitochondrial fragmentation. In accordance with their mitochondrial effects, both substances massively decreased overall, and even to a greater extent, mitochondrial ATP production decreased, as determined using a Seahorse live cell respirometer. In all these effects, DEA was more effective than AM, indicating that DEA may have higher potential in the therapy of TNBC than its parent compound.

Analysis of the Variability of the Pharmacokinetics of the Long Half-Life Drug Amiodarone in Bioequivalence Studies

The article provides an extensive analysis of the data obtained in bioequivalence studies, which can be considered for further evaluation in the development of general and individual therapeutic regimens. Concrete data obtained in two bioequivalence studies compared amiodarone formulations and included plasma levels of amiodarone and the active metabolite desethylamiodarone. The analysis included mean data and variability in plasma concentrations and pharmacokinetic parameters. In addition, a global and structural meta-analysis of the individual plasma level sets was performed. The half-life of amiodarone was not well defined and the total area below the plasma level curves was less appropriate for estimating bioequivalence.

Estimation of the In Vivo Release of Amiodarone From the Pharmacokinetics of Its Active Metabolite and Correlation With Its In Vitro Release.

Due to its very low water solubility and complex pharmacokinetics, a reliable point-to-point correlation of its in vitro release with its pharmacokinetics has not been achieved so far with amiodarone. The correlation of the in vitro dissolution of a drug with the pharmacokinetics of one of its metabolites was recently proposed by the authors of the article as an additional or alternative analysis to the usual in vitro correlations in vivo, mainly in the case of fast-absorbing drugs that have metabolites with a significant therapeutic effect. The model proposed by the authors considers that amiodarone has a slow dissolution, rapid absorption, and rapid metabolism, and before returning to the blood from other compartments, its pharmacokinetics is determined mainly by the kinetics of release in the intestine from the pharmaceutical formulation. Under these conditions, the rate of apparition of desethylamiodarone in the blood is a metric of the release of amiodarone in the intestinal fluid. Furthermore, it has been shown that such an estimated in vivo dissolution is similar, after time scaling, to the dissolution measured experimentally in vitro. Dissolution data of amiodarone and the pharmacokinetic data of its active metabolite desethylamiodarone were obtained in a bioequivalence study of 24 healthy volunteers. The elimination constant of the metabolite from plasma was estimated as the slope of the linear regression of logarithmically transformed data on the tail of plasma levels. Because the elimination of desethylamiodarone was shown to follow a monoexponential model, a Nelson–Wagner-type mass equilibrium model could be applied to calculate the time course of the “plasma metabolite fraction.” After Levi-type time scaling for imposing the in vitro–in vivo correlation, the problem became that of the correlation between in vitro dissolution time and in vivo dissolution time, which was proven to follow a square root model. To validate the model, evaluations were performed for the reference drug and test drug separately. In both cases, the scaled time for in vivo dissolution, t*, depended approximately linearly on the square root of the in vitro dissolution time t, with the two regression lines being practically parallel.

Draft of the federal clinical recommendations for diagnosisi and treatment of amiodarone-induced thyroid dysfunction

Amiodarone is an antiarrhythmic drug that is commonly used for treatment of various supraventricular and ventricular arrhythmias. Amiodarone and its main active metabolite desethylamiodarone have a direct dose-dependent cytotoxic effect on thyroid follicular cells. Consequently, some patients receiving amiodarone may develop thyroid dysfunction: amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). The diagnosis, classification, and treatment of amiodarone-induced thyroid dysfunction remain to be a challenge to all clinicians deal with this problem. This draft of clinical recommendations was developed by a group of specialists experienced in the diagnosis and treatment of amiodarone-induced thyroid dysfunction. AIH does not require amiodarone withdrawal. Thyroxine treatment is recommended for all patients with manifest AIH, subclinical forms of AIH do not always need its prescription. There are two main types of amiodarone-induced thyrotoxicosis: AIT type 1 (is a hyperthyroidism that develops due to excessive iodine intake in autonomous thyroid nodules or latent Graves ‘ disease) and AIT type 2 (develops due to destructive thyroiditis because of the cytotoxic effect of amiodarone). In addition, there is a mixed form, which has features of both types of AIT. Autonomous AIT 1 is characterized by the presence of one or more «hot» nodules in the thyroid. Elevated TSH receptor antibodies or typical clinical manifestations confirm the diagnosis of diffuse toxic goiter and, consequently, AIT1. Colour-flow Doppler sonography (CFDS) is proposed as the basic method of differential diagnosis of AIT 1 and AIT 2. CFDS «pattern 0», usually indicates AIT 2, the presence of «patterns I-III» mostly typical for AIT 1. The thyreostatics are recommended for AIT 1, oral glucocorticoids for AIT 2 and their combination for a mixed AIT. Emergency thyroidectomy should be applied to patients with deteriorating cardiovascular pathology and ineffective drug therapy. In the absence of clinical suspicion on thyroid dysfunction, thyroid hormones assessment should be done 3 months after the start of amiodarone treatment, thereafter every 6 months.

LC-MS Method for Determining Amiodarone and Desethylaminodarone in Rat Plasma Used in Endogenous Overdosing Conditions Following Lipolysis

Abstract Objective: The purpose of this study was to develop a LC-MS method to determine amiodarone (AMI) and its major metabolite desethylamiodarone (DEA) from rat plasma released from the adipose tissue of AMI treated rats subjected to a weight gain/weight loss cycle. Methods: Separation of the compounds was performed on a Kinetex 2.6 μm C18 100 x 4.6 mm column under isocratic conditions using a mixture of acetonitrile: 0.1% formic acid 65:35 at a flow rate of 0.5 ml/min. Detection of the analyte was performed by electrospray positive ionization, the monitored ions being 135 m/z from 646 for AMI and 135 m/z of 618 for DEA. Analytes were extracted after plasma protein precipitation with methanol. Results: The developed method presented specificity and linearity on the concentration range of 25-2500 ng/ml plasma for AMI and 2.5-1250 ng/ml plasma for DEA and the precision and accuracy of the method at all of quality control concentration levels including LLOQ were according to official guidelines for validating analytical methods. Conclusions: A sensitive and accurate LC-MS method has been developed with a much lower LLOQ than literature data to detect the plasma concentration differences of the studied analytes that result from forced lipolysis and mobilization from the adipose tissue.

Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro

1. Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significant effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro.2. Wild-type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10–500 μM substrate for 40 min at 37 °C and terminated at −80 °C immediately. Then these samples were treated as required and detected with ultra-performance liquid chromatography-tandem mass spectrometry used to analyze its major metabolite desethylamiodarone.3. Among the 21 CYP3A4 variants, compared with the wild-type, the intrinsic clearance values (Vmax/Km) of two variants were apparently decreased (11.07 and 2.67% relative clearance) while twelve variants revealed markedly increased values (155.20∼435.96%), and the remaining of seven variants exhibited no significant changes in enzyme activity.4. This is the first time report describing all these infrequent alleles for amiodarone metabolism, which can provide fundamental data for further clinical studies on CYP3A4 alleles.

Therapeutic Drug Monitoring of Amiodarone and Desethylamiodarone

Amiodarone (AM) is used for the treatment of cardiac arrhythmias. European guidelines recommend amiodarone dosage 200-400 mg/day for long-term prevention of arrhythmias. Therapeutic drug monitoring (TDM) is a part of clinical practise in cardiology although the association between AM and DEA plasma concentrations/dose and clinical efficacy/toxicity is still unclear. Plasma concentrations of both AM and DEA ranging between 0.5-2.5 mg/L were most often observed in patients responded to AM therapy. We analyzed retrospectively trough levels of AM and DEA measured by high performance liquid chromatography method with UV detection in years 2013-2015. The dose of AM per kilogram of body weight needed to reach AM level of 1 mg/L was calculated and results were compared with real levels to evaluate compliance of patients. We compared also concentrations of AM and DEA in relation to recommended AM dosage and determined possible non-compliance by calculation of AM clearance. Amiodarone was prescribed on average dose 226 mg/day and 2.8 mg/kg/day. Measured concentrations ranged from 0.17 to 2.49 mg/L (median 0.67 mg/L) for AM and between 0.14-1.67 mg/L (median 0.62 mg/L) for DEA. Supposed therapeutic effective levels of 0.5 mg/L were not reached in 131 patients (30%) for AM and 178 patients (40%) for DEA. 159 patients (36%) of them were probably underdosed (especially with AM dose 100-200 mg/day) and 19 patients (4%) were likely non-compliant. Only 60% of patients reached supposed minimally therapeutic effective levels of AM or DEA, 36% of them was underdosed and 4% of patients was likely non-compliant. Therefore routine TDM of amiodarone including its active metabolite desethylamiodarone may help to achieve optimal dosage of amiodarone.

Analysis of Pharmacokinetic Interaction Between Amiodarone/Desethylamiodarone and Metoprolol

Amiodarone (AM) is the most effective antiarrhythmic drug and its major metabolite desethylamiodarone (DEA) is pharmacologically effective as well. A β1 blocker metoprolol (M) is metabolized to alpha-hydroxymetoprolol (OH-M) by CYP2D6 and both AM and DEA inhibit this enzyme. We analysed interaction between amiodarone/ desethylamiodarone and metoprolol. We analyzed retrospectively 69 serum concentrations of AM, DEA, M and OH-M measured by HPLC method with UV or fluorescent detection from 29 patients (years 2014-2015). We estimated the concentration/dose ratio of metoprolol, metabolic ratio of M/OH-M and OH-M/M, and metoprolol clearance (Cl) and elimination half-time (t1/2) depending on concentrations of AM, DEA and sum AM+DEA. Phenotypization of patients was performed by metabolic ratio (MR) of M/OH-M concentrations. Statistically significant correlation was observed between concentration/dose ratio of metoprolol and concentrations of both AM and DEA as well as between metabolic ratio M/OH-M and concentrations of both sum AM+DEA and DEA itself. No statistically significant correlation was found between t1/2 a Cl of metoprolol and concentrations of AM or DEA. Phenotypization of CYP2D6 divided individual samples into groups with MR<1.0 (n=17) and MR 1.0-10.5 (n=7) for serum taking after metoprolol administration and with MR<1.0 (n=31) and MR 1.0-10.5 (n=7) for serum taking before metoprolol administration. We showed that an increasing concentrations of amiodarone and desethylamiodarone led to lower dose of metoprolol to achieved the same serum concentration. Increase of DEA and sum of AM+DEA concentrations led to decrease of metoprolol metabolization by inhibition of CYP2D6. The results indicate that important drug-drug interaction between metoprolol and amiodaron is due to inhibition of CYP2D6, mainly by DEA. Therefore wen the combination of drugs is administered careful therapeutic monitoring of not only metoprolol but also of amiodarone including DEA is recommended.

Pharmacokinetic Interaction Between Digoxin and Amiodarone

Digoxin and amiodarone (AM) are used in therapy of atrial fibrillation. Amiodarone and its active metabolite desethylamiodarone (DEA) inhibit P-glycoprotein system and increase serum levels of digoxin with the risk of intoxication. Trough levels of digoxin (MEIA method) and AM including DEA (HPLC method) were analyzed in 322 patients in years 2007-2015 and analyzed retrospectively. Patients were divided in 4 groups according to AM levels and sum of AM+DEA levels (<0.5 mg/L, 0.5-1.0 mg/L, 1.0-2.0 mgl/L, >2.0 mg/L), in 3 groups according to DEA levels (<0.5 mg/L, 0.5-1.0 mg/L, >1 mg/L) and in 4 groups according to DEA/AM ratio (<0.5, 0.5-1.0, 1.0-1.5, >1.5). Control group consists of 2792 patients treated by digoxin itself. We observed relationship between concentration/dose (C/D) ratio of digoxin and concentration of AM, DEA, their ratio and summation. Statistically significant decrease of normalized daily dose of digoxin were observed in groups of patients with AM levels from 1.0 to 2.0 mg/L (about 21%) and >2.0 mg/L (about 15 %), with DEA levels from 0.5 to 1.0 mg/L (about 9%) and >1 mg/L (about 39%), with DEA/AM ratio from 0.5 to 1.0 (about 11.5%) and with sum of AM+DEA >2.0 mg/L (about 23%). We determined statistically significant correlation between C/D ratio of digoxin and AM concentration, DEA concentration and sum of AM+DEA. Any statistically significant correlation was not observed between C/D ratio of digoxin and DEA/AM ratio. We demonstrated that lower dose of digoxin is needed to reach the same level if the concetrations of AM (>1.0 mg/L), DEA (>0.5 mg/L) and their summation (>2.0 mg/L) is growing. Therapeutic drug monitoring of both drugs including DEA is an adequate method for dosage optimalization if the combination of digoxin and amiodarone is administered.

Therapeutic monitoring of amiodarone: pharmacokinetics and evaluation of the relationship between effect and dose/concentration

Amiodarone is the most effective agent in the therapy of arrhythmias. However, the clinical effect of acute and chronic treatment is unclear and there are differences irrespective of comparable plasma/myocardial amiodarone and its metabolite desethylamiodarone concentations as well. Its unusual pharmacokinetics results in interindividual variation in plasma levels. The association between amiodarone and desethylamiodarone plasma levels and clinical efficacy is difficult to evaluate. This review was carried out to assess whether there is any objective correlation between amiodarone and desethylamiodarone plasma levels and the clinical effect. We summarized the results of relevant studies and clarified the relationship between plasma levels and effect vis á vis the pharmacokinetics and pharmacogenetics of this drug. Certain correlation was seen with oral amiodarone therapy, in others, plasma amiodarone levels were unrelated to therapeutic response and showed no correlation with changes in electrocardiogram or electrophysiological parametres. Several studies show that plasma concentration ranging between 0.5 and 2.5 mg/L appears to be the most effective, others demonstrate no difference between responders and non-responders. One way of interpreting plasma levels is to establish an individual patient´s effective concentration. Therapeutic drug monitoring can contribute to determining optimal concentration.

A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data

Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug's therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug-metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. The developed PBPK model can be regarded as the first step towards a PBPK-pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.

Long-term pretreatment with desethylamiodarone (DEA) or amiodarone (AMIO) protects against coronary artery occlusion induced ventricular arrhythmias in conscious rats.

The aim of this investigation was to compare the effectiveness of long-term pretreatment with amiodarone (AMIO) and its active metabolite desethylamiodarone (DEA) on arrhythmias induced by acute myocardial infarction in rats. Acute myocardial infarction was induced in conscious, male, Sprague-Dawley rats by pulling a previously inserted loose silk loop around the left main coronary artery. Long-term oral pretreatment with AMIO (30 or 100 mg·(kg body mass)(-1)·day(-1), loading dose 100 or 300 mg·kg(-1) for 3 days) or DEA (15 or 50 mg·kg(-1)·day(-1), loading dose 100 or 300 mg·kg(-1) for 3 days), was applied for 1 month before the coronary artery occlusion. Chronic oral treatment with DEA (50 mg·kg(-1)·day(-1)) resulted in a similar myocardial DEA concentration as chronic AMIO treatment (100 mg·kg(-1)·day(-1)) in rats (7.4 ± 0.7 μg·g(-1) and 8.9 ± 2.2 μg·g(-1)). Both pretreatments in the larger doses significantly improved the survival rate during the acute phase of experimental myocardial infarction (82% and 64% by AMIO and DEA, respectively, vs. 31% in controls). Our results demonstrate that chronic oral treatment with DEA resulted in similar cardiac tissue levels to that of chronic AMIO treatment, and offered an equivalent degree of antiarrhythmic effect against acute coronary artery ligation induced ventricular arrhythmias in conscious rats.

Amiodarone and the thyroid dysfunction

Amiodarone, a class III antiarrhytmic agent, is a benzofuran derivative containing 75 mg iodide per 200 mg tablet. During the metabolism of 200 mg of the drug approximately 6-8 mg of inorganic iodine is released into the systemic circulation. Amiodarone is very lipophilic and concentrates in various tissues and organs such as adipose tissue, skeletal muscles, myocardium, liver, lung and thyroid. Amiodarone is dealkylated in the liver to its major active metabolite desethylamiodarone. Amiodarone therapy is associated with a number of side effects, including thyroid dysfunction – thyrotoxicosis in 2-15% and hypothyroidism in 5-20% of patients, respectively. The effects of amiodarone on thyroid function depend on underlying thyroid status and dietary iodine intake. Patients with autoimmune thyroid disease are more likely to develop hypothyroidism due to failure to escape from Wolff-Chaikoff effect. In patients with multinodular goiter or latent Graves’ disease hyperthyroidism may occur. Amiodarone may also cause destructive thyroiditis in patients without underlying thyroid disease. Thyrotoxicosis may be a result of increased synthesis of thyroid hormones (type 1) or of their excessive release due to a direct damage of thyroid cells caused by amiodarone, its metabolite desethylamiodarone or iodine (type 2). The distinction between type 1 and type 2 thyrotoxicosis is crucial, since therapy is different in these two types. The differential diagnosis is based on the presence of goiter, evaluation of thyroid autoantibodies, colour flow Doppler image, thyroid uptake and on the response to steroids or perchlorate. Patients with type 1 thyrotoxicosis require thionamides or potassium/sodium perchlorate, while those with type 2 – corticosteroids. Hypothyroidism is treated with L-thyroxine. The signs and symptoms of amiodarone-induced thyrotoxicosis and hypothyroidism can be scanty. Therefore, all patients treated with amiodarone need periodic examination of thyroid function. Apart from inducing thyroid dysfunction, amiodarone causes hypercholesterolemia due to decreased expression of the LDL receptor gene, which is regulated by T3. Adverse effects of amiodarone have led to the search for analogues with the same efficacy but safer profile. Dronedarone is structurally related to amiodarone but does not contain iodine atoms and does not increase the incidence of thyroid disease. Dronedarone appears to be less-effective but may be beneficial for patients with atrial fibrillation or flutter who are at risk of developing amiodarone induced thyroid dysfunction.

Letter to the Editor Amiodarone-induced thyrotoxicosis with paroxysmal supraventricular (ectopic atrial) tachycardia: and review of the literature

Letter to the Editor Amiodarone-induced thyrotoxicosis with paroxysmal supraventricular (ectopic atrial) tachycardia: and review of the literature

First liquid chromatographic method for the simultaneous determination of amiodarone and desethylamiodarone in human plasma using microextraction by packed sorbent (MEPS) as sample preparation procedure

For the first time a simple and fast high-performance liquid chromatography (HPLC) method using a novel sample preparation procedure based on microextraction by packed sorbent (MEPS) was developed and validated for the determination of amiodarone (AM) and its main metabolite desethylamiodarone (DEA) in human plasma. Chromatographic separation of the analytes (AM and DEA) and tamoxifen, used as internal standard (IS), was achieved within less than 5min on a LiChroCART Purospher® Star C18 column (55mm×4mm, 3μm). The mobile phase consisting of 50mM phosphate buffer with 0.1% formic acid (pH 3.1)/methanol/acetonitrile (45:5:50, v/v/v) was pumped isocratically at a flow rate of 1.2mL/min. The detection was carried out at 254nm. Calibration curves were linear (r2≥0.9976) in the ranges of 0.1–10μg/mL for AM and DEA. The limits of quantification were established at 0.1μg/mL for AM and DEA. The overall imprecision did not exceed 6.67% and inaccuracy was within ±9.84%. The overall mean recovery of AM and DEA ranged from 58.6% to 68.2%. Neither endogenous nor tested exogenous compounds were found to interfere at retention times of the analytes (AM and DEA) and IS. This new MEPS/HPLC method was also applied to real samples obtained from polymedicated patients receiving AM therapy. Thus, this bioanalytical method seems to be a useful tool for therapeutic drug monitoring of patients under AM treatment and also to support other clinical pharmacokinetic-based studies involving this drug, such as bioavailability/bioequivalence studies.

Simultaneous measurement of amiodarone and desethylamiodarone in human plasma and serum by stable isotope dilution liquid chromatography–tandem mass spectrometry assay

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 μg/L for amiodarone and 1.9 μg/L for desethylamiodarone, and lower limits of quantification in plasma matrix were 7.5 μg/L for amiodarone and 2.5 μg/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.

Benzofuran derivatives and the thyroid

Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three decades. However amiodarone and its main metabolically active metabolite desethylamiodarone can adversely affect many organs, including the thyroid gland. Amiodarone-induced thyroid disorders are common and often present as a management challenge for endocrinologists. The pathogenesis of amiodarone-induced thyroid dysfunction is complex but the inherent effects of the drug itself as well as its high iodine content appear to play a central role. The non-iodinated dronedarone also exhibits anti-arrhythmic properties but appears to be less toxic to the thyroid. This review describes the biochemistry of benzofuran derivatives, including their pharmacology and the physiology necessary for understanding the cellular mechanisms involved in their actions. The known effects of these compounds on thyroid action are described. Recommendations for management of amiodarone-induced hypothyroidism and thyrotoxicosis are suggested. Dronedarone appears to be an alternative but less-effective anti-arrhythmic agent and it does not have adverse effects on thyroid function. It may have a future role as an alternative agent in patients being considered for amiodarone therapy especially those at high risk of developing thyroid dysfunction but not in severe heart failure.

Effects of intestinal constituents and lipids on intestinal formation and pharmacokinetics of desethylamiodarone formed from amiodarone

Abstract To model the impact of intestinal components associated with a high fat meal on metabolism of amiodarone, rat everted intestinal sacs were evaluated for their ability to metabolize the drug to its active metabolite (desethylamiodarone) under a variety of conditions. The preparations were obtained from fasted rats or rats pretreated with 1% cholesterol in peanut oil. After isolation of the tissues, the intestinal segments were immersed in oxygenated Krebs Henseleit buffer containing varying concentrations of bile salts, cholesterol, lecithin and lipase with or without soybean oil emulsion as a source of triglycerides. Amiodarone uptake was similar between the five 10-cm segments isolated distally from the stomach. Desethylamiodarone was measurable in all segments. Based on the metabolite-to-drug concentration ratio within the tissues, there was little difference in metabolic efficiency between segments for any of the treatments. Between treatments, however, it appeared that the lowest level of metabolism was noted in rats pretreated with 1% cholesterol in peanut oil. This reduction in metabolic efficiency was not observed in gut sacs from the fasted rats to which soybean oil emulsion was directly added to the incubation media. Despite the apparent reduction in intestinal metabolism, there was no apparent change in the ratio of metabolite-to-drug area under the plasma concentration versus time ratios of fasted rats and those given 1% cholesterol in peanut oil, suggesting that the intestinal presystemic formation of desethylamiodarone is not substantial.

Effects of intestinal constituents and lipids on intestinal formation and pharmacokinetics of desethylamiodarone formed from amiodarone

To model the impact of intestinal components associated with a high fat meal on metabolism of amiodarone, rat everted intestinal sacs were evaluated for their ability to metabolize the drug to its active metabolite (desethylamiodarone) under a variety of conditions. The preparations were obtained from fasted rats or rats pretreated with 1% cholesterol in peanut oil. After isolation of the tissues, the intestinal segments were immersed in oxygenated Krebs Henseleit buffer containing varying concentrations of bile salts, cholesterol, lecithin and lipase with or without soybean oil emulsion as a source of triglycerides. Amiodarone uptake was similar between the five 10-cm segments isolated distally from the stomach. Desethylamiodarone was measurable in all segments. Based on the metabolite-to-drug concentration ratio within the tissues, there was little difference in metabolic efficiency between segments for any of the treatments. Between treatments, however, it appeared that the lowest level of metabolism was noted in rats pretreated with 1% cholesterol in peanut oil. This reduction in metabolic efficiency was not observed in gut sacs from the fasted rats to which soybean oil emulsion was directly added to the incubation media. Despite the apparent reduction in intestinal metabolism, there was no apparent change in the ratio of metabolite-to-drug area under the plasma concentration versus time ratios of fasted rats and those given 1% cholesterol in peanut oil, suggesting that the intestinal presystemic formation of desethylamiodarone is not substantial.

Simultaneous determination of amiodarone and its metabolite desethylamiodarone by high-performance liquid chromatography with chemiluminescent detection

A novel method was developed for the determination of amiodarone and desethylamiodarone by high-performance liquid chromatography (HPLC) coupled with chemiluminescent (CL) detection. The procedure is based on the post-column photolysis of the analytes into photoproducts which are active in the tris(2,2′-bipyridyl)ruthenium(III) [Ru(bpy) 3 3+] CL system. Ru(bpy) 3 3+ was on-line generated by photo-oxidation of the Ru(II) complex in the presence of peroxydisulfate. The separation was carried out on a Mediterranea C 18 column with isocratic elution using a mixture of methanol and 0.017 mol L −1 ammonium sulfate buffer of pH 6.8. Under the optimum conditions, analytical curves, based on standard solutions, were linear over the range 0.1–50 μg mL −1 for amiodarone and 0.5–25 μg mL −1 for desethylamiodarone. The detection limits of amiodarone and desethylamiodarone were 0.02 and 0.11 μg mL −1, respectively. Intra- and inter-day precision values of 0.9% relative standard deviation (R.S.D.) ( n = 10) and 1.6% R.S.D. ( n = 15), respectively, were obtained. The method was applied successfully to the determination of these compounds in serum and pharmaceutical formulations.