Plasma Amiodarone Research Articles

Implications of Incorporating Plasma Lipoprotein Binding into a Physiologically-Based Pharmacokinetic Model: A Simulation Study with Amiodarone.

Although various lipophilic drugs are bound to lipoproteins, lipoprotein binding in plasma is not usually considered in current physiologically-based pharmacokinetic (PBPK) models. Amiodarone is extensively bound to serum triglyceride-rich lipoproteins. Total plasma amiodarone concentration, which is the sum of both unbound and bound concentrations, increases with increasing serum triglyceride levels. We investigated the impact of lipoprotein binding on amiodarone pharmacokinetics using PBPK modeling and simulations. An amiodarone PBPK model that incorporates plasma lipoprotein binding (LPP model) was developed based on the correlation between serum triglyceride levels and lipoprotein-bound amiodarone. The predicted unbound fraction of amiodarone in plasma and systemic clearance in the LPP and base models (with albumin binding only) were similar, but the coefficients of variation for the LPP model were greater than those for the base model and were closer to the observed data. The total plasma amiodarone concentration predicted using the LPP model increased with higher levels of plasma lipoprotein binding and serum albumin. In contrast, changes in plasma lipoprotein binding and serum albumin levels did not influence the predicted unbound plasma amiodarone concentration at steady-state. This study demonstrates that incorporating plasma lipoprotein binding into a PBPK model improves the accuracy of predicting interindividual variabilities in amiodarone clearance by more reliably predicting the interindividual variability in the plasma unbound fraction of amiodarone. Plasma lipoprotein binding should be considered in PBPK modeling and simulations for lipoprotein-associated drugs if there is available information on the relationship between plasma lipoprotein binding and hyperlipidemia.

Amiodarone/N-desethylamiodarone population pharmacokinetics in paediatric patients.

The population pharmacokinetics of amiodarone and its active metabolite, N-desethylamiodarone (DEA) were investigated in paediatric patients with arrhythmias, mainly supraventricular tachycardias. A total of 55 patients from the Department of Pediatric Intensive Care and Pediatric Cardiology at Necker-Enfants malades Hospital (Paris, France) provided 72 concentrations for both amiodarone and DEA following repeated oral or intravenous administration. Blood samples drawn for biological analyses were used for drug concentrations. Plasma amiodarone concentrations were measured by a liquid chromatography method coupled with mass spectrometry and the data were modelled using the software Monolix 2019R2. Parent pharmacokinetics was described with a 2-compartment open model and the metabolite formation was connected to the central parent compartment. Parameter estimates scaled allometrically on bodyweight (normalized to 70 kg) were, respectively (% relative standard errors, RSEs), 6.32 (31%) and 7.14 L/h (26%) for elimination (CL) and intercompartmental clearances and 167 (31%) and 3930 (32%) L for V1 and V2 . Oral bioavailability was 0.362 (21.5%). The clearance between subject variability (ω, square root of the variance) was 0.462 (RSE 21%). The proportional residual variabilities were respectively 0.453 (RSE 13%) and 0.423 (RSE 12%) for amiodarone and DEA respectively. The terminal half-lives were 34 and 14.5days for amiodarone and DEA, respectively. A dosage schedule was established for 3 weight bands in 2 time periods. The high pharmacokinetic variability suggests that therapeutic drug monitoring might be useful to improve individual efficacy and safety.

Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside.

Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. Methods: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters Cmax, Tmax AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. Results: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of Cmax in the VV ECMO group as compared to controls. No difference in Tmax was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. Conclusions: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

Influence of concomitant medication on plasma concentration of amiodarone in patients with atrial fibrillation - a pilot study.

BackgroundAlthough amiodarone is a drug with many side effects, it is one of the most commonly used drugs in the treatment and prophylaxis of supraventricular and ventricular arrhythmias.AimThe purpose of this pilot study was to evaluate plasma concentrations of amiodarone in patients with atrial fibrillation (AF) and to identify possible drug-drug interactions between amiodarone and concomitant medications.MethodA prospective observational study was conducted in 27 consecutive patients treated with amiodarone from May to July 2017 in a Clinical University Hospital. The patients included met our inclusion criteria. HPLC-UV was the device used to determine the plasma concentration of amiodarone.ResultsOnly 51.8% of the patients had amiodarone plasma concentration within therapeutic interval (500–2500 ng/ml). The drugs associated to amiodarone in the therapeutic plan were diuretics, beta blockers, statins, antiplatelets, fluoroquinolones, non-steroidal anti-inflammatory drugs. We observed a statistically significant difference between the plasmatic concentrations of amiodarone in patients treated with furosemide vs. patients concomitantly treated with other drugs. Interactions between other mentioned drugs and amiodarone were not registered. We can report an underuse of amiodarone for more than 50% of the patients. Also, we found a significant interaction between furosemide and amiodarone, most likely through the interaction with MDR.ConclusionFurosemide may influence the pharmacokinetics of P-gp-interfering drugs. However, the relevance of these findings needs to be confirmed and further research is needed to characterize the interaction between amiodarone and furosemide.

Dietary-Induced Obesity and Changes in the Biodistribution and Metabolism of Amiodarone in the Rat

The metabolism and biodistribution of the antiarrhythmic drug amiodarone (AM) was assessed in male Sprague-Dawley rats given either normal chow or high-fat and high-fructose diets for 14 weeks. After the feeding period, microsomes were prepared from liver and intestine, and the metabolism of AM to desethylamiodarone was determined. Intrinsic clearance (CL) was reduced by hepatic microsomes isolated from rats given high-calorie diets. In intestinal microsomes, there was no change or a small increase in metabolic rate in obese rats. A biodistribution study was also undertaken in a group of control and high-fat + high fructose-fed rats. Excess calories led to a significant increase in plasma AM compared to normal chow-fed control animals. A population pharmacokinetic analysis of AM confirmed that its oral CL was reduced. In plasma, there was a decrease in the metabolite to drug ratio. Some tissue:plasma ratios of AM in high calorie-fed rats were aligned with a decrease in plasma unbound fraction. It is concluded that the findings reinforced those of a recent report where we found decreases in expressions of enzymes involved in AM dealkylation, in showing greater exposure and lower oral CL, and generally decreases in liver microsomal metabolism of AM after high-calorie diets.

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.

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.

Clinical efficacy of epicardial application of drug-releasing hydrogels to prevent postoperative atrial fibrillation

ObjectivePostoperative atrial fibrillation is the most frequent complication arising after cardiac surgery, occurring in 40% of cases. The treatment of postoperative atrial fibrillation with epicardial amiodarone/corticosteroid hydrogel delivery can increase efficacy and reduce side effects. To further evaluate whether amiodarone hydrogel is superior to corticosteroid hydrogel or placebo, we performed a randomized prospective study in 150 patients with coronary artery bypass grafting to compare the effectiveness with different epicardial drug approaches in the postoperative period. MethodsAfter institutional review board approval, 150 patients, from January 2012 to July 2014, who had undergone cardiac surgery were randomized to 3 equal groups. Group I received poly-based hydrogel with amiodarone, and group II received poly-based hydrogel with triamcinolone. Both hydrogels were sprayed diffusely over the biatrial epicardium. The control group underwent the procedure with only hydrogel spray. Continuous telemetry monitored for postoperative atrial fibrillation, and amiodarone or triamcinolone levels in the atria, plasma, and tissue were measured postoperatively. Daily electrocardiographic parameters were measured until postoperative day 14. ResultsThe incidence of postoperative atrial fibrillation was significantly less in group I, with 4 of 50 patients (8%) incurring atrial fibrillation compared with 11 of 50 patients (22%) in group II and 13 of 50 patients (26%) in the control group (P < .01). The mean amiodarone and triamcinolone concentrations in the atria (12.06 ± 3.1/1.5 ± 0.7) were significantly greater than those in the extracardiac tissues (1.32 ± 0.9/0.2 ± 0.4; P < .01). The plasma amiodarone and triamcinolone levels remained below the detection limit (<8 μg/mL and <0.2 μg/mL) during the 14 days of follow-up. Bradycardia was observed less in the control group (93 ± 18) than in study group I (76 ± 29; P < .01). ConclusionsEpicardial application of amiodarone-releasing adhesive hydrogel is a less-invasive, well-tolerated, quick, and effective therapeutic option for preventing postoperative atrial fibrillation with minimal risk of extracardiac adverse side effects. However, there was no clinical evidence that epicardial corticosteroid prevented postoperative atrial fibrillation.

Effectiveness of biatrial epicardial application of amiodarone-releasing adhesive hydrogel to prevent postoperative atrial fibrillation

Postoperative atrial fibrillation (POAF) is the most frequent complication arising after cardiac surgery, occurring in 30% of cases. Amiodarone is the most effective drug for prophylaxis and treatment. However, because of significant extracardiac side effects, only high-risk patients are eligible for prophylactic amiodarone therapy. We performed a randomized prospective study of 100 patients undergoing cardiac surgery with epicardial application of amiodarone-releasing hydrogel to determine the effectiveness of preventing POAF. After institutional review board approval, 100 patients, from January 2012 to July 2013, who had undergone cardiac surgery, were randomized to 2 equal groups. The study group received poly-based hydrogel with amiodarone sprayed diffusely over the epicardium. The control group underwent the procedure without the spray. Continuous telemetry monitored for POAF, and amiodarone levels in the atria, plasma, and tissue were measured postoperatively. Daily electrocardiographic parameters were measured until postoperative day 14. The incidence of POAF was significantly less in the study group, with 4 of 50 patients (8%) incurring atrial fibrillation compared with 13 of 50 patients (26%) in the control group (P < .01). The mean amiodarone concentrations in the atria (12.06 ± 3.1) were significantly greater than those in the extracardiac tissues (1.32 ± 0.9; P < .01). The plasma amiodarone levels remained below the detection limit (<8 μg/mL) during the 14 days of follow-up. Bradycardia was observed less in the study group (76 ± 29) than in the control group (93 ± 18; P < .01). Epicardial application of amiodarone-releasing adhesive hydrogel is a less invasive, well-tolerated, quick, and effective therapeutic option for preventing POAF at minimal risk of extracardiac adverse side effects.

Amiodarone toxicity showing high liver density on CT scan with normal liver function and plasma amiodarone levels in a long-term amiodarone user

Amiodarone toxicity showing high liver density on CT scan with normal liver function and plasma amiodarone levels in a long-term amiodarone user

Comparative Bioavailability Study with Two Amiodarone Tablet Formulations Administered with and without Food in Healthy Subjects

The aim was to assess the comparative bioavailability of two formulations (200 mg tablet) of amiodarone (CAS 19774-82-4) in healthy volunteers of both sexes, with and without food. The study was conducted using an open, randomized, two-period crossover design with a 3-week washout interval, in two groups, with and without food. Plasma samples were obtained for up to 240 h post dose. Plasma amiodarone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). From the amiodarone plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained, with and without food: AUC(last), AUC(inf), AUC(0-240h), AUC(0-72h) and C(max). The limit of quantification was 1 ng/mL for plasma amiodarone analysis. The geometric mean and 90% confidence interval CI of Test/Reference percent ratios were, without and with food, respectively: 107.61 (92.73-124.89) and 100.6 (94.1-107.5) for C(max), 107.05 (95.88-119.51) and 100.2 (96.0-104.7) for AUC(last), 107.27 (95.78-120.15) and 100.8 (97.0-104.8) for AUC(0-72h), 106.76 (95.84-118.94) and 100.2 (96.0-104.7) for AUC(0-240h) and AUC(inf) 105.15 (94.18-117.41) and 100.7 (96.6-105.0). Since the 90% CI for AUC(0-72) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that the amiodarone 200 mg tablet (test formulation) with and without food was bioequivalent to the reference 200 mg tablet for both the rate and extent of absorption.

Comparative analysis of the experimental and clinical pharmacokinetics of Amiodarone

The pharmacokinetics of two tablet formulations of amiodarone – Amiodarone and Amiodaron-Akri – were studied in 12 rabbits and 18 healthy human volunteers after single p.o. doses of 200 mg. A highly statistically significant correlation was found between plasma amiodarone concentrations in rabbits and volunteers (r = 0.8263, p < 0.001). Normalized C max and AUC 0−∞ values were significantly greater in volunteers than rabbits, while specific V Z and Cl t values were lower and MRT was significantly higher; rate coefficients of absorption and measures of relative bioavailability showed no statistically significant differences between rabbits and healthy humans.

Amiodarone and desethylamiodarone tissue uptake in rats chronically treated with amiodarone is non-linear with the dose

Four groups of rats were given amiodarone chronically at 25, 37.5, 50, 75 mg kg-1/12 h for 3 weeks; on day 21 the animals were killed and blood, plasma, heart, lung, liver and fat were collected and assayed for amiodarone and desethylamiodarone. Amiodarone plasma concentrations ranged from 0.74 to 4.68 micrograms mL-1 and desethylamiodarone from 0.08 to 2.05 micrograms mL-1. Plasma, blood and tissue concentrations of amiodarone and desethylamiodarone increased significantly with the dose. Blood/plasma and tissue/plasma partition ratios of amiodarone and desethylamiodarone increased significantly at the higher doses. Blood/plasma ratio was a good predictor of tissue/plasma ratios of amiodarone and its metabolite, except in fat. Total phospholipid concentrations in lung were correlated with amiodarone and desethylamiodarone concentrations in plasma, blood and lung.

Effects of neferine on the pharmacokinetics of amiodarone in rats

Amiodarone, an iodinated benzofuran derivative with predominantly class III anti-arrhythmic effects, is used to treat supraventricular and ventricular arrhythmias. The purpose of this study was to assess the potential of neferine, an effective anti-pulmonary fibrosis drug isolated from the embryo of Nelumbo nucifera Gaertner's seeds, to alter the pharmacokinetic profile of amiodarone. Experimental Sprague-Dawley rats were randomly divided into two groups. In groups 1 and 2, amiodarone was given to rats by intragastric and intravenous administration, respectively, while neferine was co-administratered by intragastric administration. Blood samples were collected from the orbital venous plexus at indicated time points and were analyzed for amiodarone concentration using RP-HPLC. The geometric mean ratio for C(max) and AUC(0-96) was calculated. There were no significant differences between the pharmacokinetics parameters of amiodarone administered intravenously or intragastrically and the control (without neferine) group (with ratios of 0.7-1.4 in all experimental groups), suggesting that neferine had no effect on amiodarone plasma pharmacokinetics. The dosage regimen of amiodarone does not need to be taken into consideration when combined with neferine.

Intravenous Lipid Emulsion Sequesters Amiodarone in Plasma and Eliminates Its Hypotensive Action in Pigs

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. 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. 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). 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.

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias

Background Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. Methods Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1 mg/kg bw) ( n = 10) or without drug ( n = 6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28 days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. Results The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21 days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced ( P < 0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (< 10 ng/mL) during the 28-day follow-up. Conclusions Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3 weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.

Bioequivalence of 2 Intravenous Amiodarone Formulations in Healthy Participants

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight participants were enrolled in this randomized, double-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The amiodarone plasma concentration-time curve observed with both formulations was virtually identical, as was the 72-hour area under the curve (AUC0-72). Similar equivalence was seen for desethylamiodarone, the active metabolite of amiodarone. The geometric ratios of the AUC0-72 for amiodarone and desethylamiodarone were 1.03 (95% confidence interval [CI], 1.00-1.06) and 1.01 (0.99-1.03), respectively. Similar geometric ratios and CIs were found for maximum plasma concentration (Cmax) and for AUC extrapolated to infinity (AUC0-infinity). Because the ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to PM101 were identified.

Experimental Hyperlipidemia Causes an Increase in the Electrocardiographic Changes Associated With Amiodarone

To assess the influence of hyperlipidemia (HL) on amiodarone (AM) effect in the heart, rats were pretreated with either 1 g/kg poloxamer 407 (to induce HL) or saline intraperitoneally. At approximately 36 hours afterward, rats were given AM HCl (25, 50, and 100 mg.kg.d) or saline intravenously through implanted venous cannulas for 5 days. Under anesthesia, electrocardiogram (ECG) was recorded using subcutaneous electrodes and blood samples were withdrawn at baseline and 12 hours after the first, middle, and last doses. At the end of the study, heart tissues were collected. Specimens were analyzed for AM and desethylamiodarone. HL by itself did not alter the ECG. Compared with baseline, the end of study prolongation of QTc and PR intervals were significantly (P < 0.05) higher in all AM-treated HL rats. AM plasma and heart concentrations in HL rats after the last dose were significantly (P < 0.05) higher than in normolipidemic rats. Similar to AM, in HL rats, plasma desethylamiodarone after the last dose was significantly higher than in normolipidemic rats. The cholesterol to triglyceride plasma ratio was linearly related to QT interval and plasma and heart AM concentrations. HL increased the ECG effects of AM by increasing heart concentrations.

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

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.

In Vivo Electropharmacological Effects of Amiodarone and Candesartan on Atria of Chronic Atrioventricular Block Dogs

Electropharmacological effects of chronically administered amiodarone and candesartan on atria that had been remodeled against congestive heart failure were assessed using dogs (about 10 kg in weight) with chronic atrioventricular block. Amiodarone was administered orally in a dose of 200 mg/body per day for the initial 7 days followed by 100 mg for the following 21 days (n = 7). Candesartan was administered in a dose of 12 mg/body per day for 28 days (n = 7). All animals survived the 4-week experimental period, indicating the lack of risks for inducing cardiohemodynamic collapse or torsade de pointes by these drugs. The plasma amiodarone concentration was 353 ng/ml at 4 weeks of treatment. Before candesartan treatment (control), intravenous administration of 30 ng/kg of angiotensin II increased the mean blood pressure by 18 mmHg, which was significantly decreased to 1 mmHg by 4 weeks of treatment. Amiodarone prolonged the atrial effective refractory period without affecting inter-atrial conduction time and decreased the duration of the burst pacing-induced atrial fibrillation, whereas candesartan hardly affected these variables. These results indicate that amiodarone should become a pragmatic pharmacological strategy against atrial fibrillation in patients with chronically compensated heart failure and suggest that a much higher dose of candesartan may be needed to exert its efficacy in this model.