Direct analysis in real time-mass spectrometry for rapid quantification of five anti-arrhythmic drugs in human serum: application to therapeutic drug monitoring.

Therapeutic drug monitoring (TDM) is necessary for the optimal administration of anti-arrhythmic drugs in the treatment of heart arrhythmia. The present study aimed to develop and validate a direct analysis in real time tandem mass spectrometry (DART-MS/MS) method for the rapid and simultaneous determination of five anti-arrhythmic drugs (metoprolol, diltiazem, amiodarone, propafenone, and verapamil) and one metabolite (5-hydroxy(OH)-propafenone) in human serum. After the addition of isotope-labeled internal standards and protein precipitation with acetonitrile, anti-arrhythmic drugs were ionized by DART in positive mode followed by multiple reaction monitoring (MRM) detection. The use of DART-MS/MS avoided the need for chromatographic separation and allowed rapid and ultrahigh throughput analysis of anti-arrhythmic drugs in a total run time of 30 s per sample. The DART-MS/MS method yielded satisfactory linearity (R2 ≥ 0.9906), accuracy (86.1-109.9%), and precision (≤ 14.3%) with minimal effect of biological matrixes. The method was successfully applied to analyzing 30 clinical TDM samples. The relative error (RE) of the concentrations obtained by DART-MS/MS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was within ± 13%. This work highlights the potential usefulness of DART for the rapid quantitative analysis of anti-arrhythmic drugs in human serum and gives rapid feedback in the clinical TDM practices.

Drug-Drug Interactions Of Amiodarone And Quinidine On The Pharmacokinetics Of Eliglustat In Rats.

BACKGROUND: Eliglustat, a new oral substrate-reduction therapy, was recently approved as a first-line therapy for Gaucher's disease type 1 (GD1) patients. PURPOSE: The purpose of the present study was to develop and validate a simple UPLC-MS/MS method for the measurement of plasma-eliglustat concentration and to investigate the effects of amiodarone and quinidine on eliglustat metabolism in rats. METHODS: Eighteen rats were randomly divided into three groups (n=6): control (0.5% CMC-Na, group A), amiodarone (60 mg/kg, group B), and quinidine (100 mg/kg, group C). Thirty minutes later, 10 mg/kg eliglustat was orally administered to each rat and concentrations of eliglustat in the rats determined by our UPLC-MS/MS method. RESULTS: Amiodarone and quinidine increased the main pharmacokinetic parameters (AUC0→ t , AUC0→∞, and Cmax) of eliglustat significantly and decreased clearance obviously. CONCLUSION: Amiodarone and quinidine can elevate eliglustat exposure and have an inhibitory effect on eliglustat metabolism. Clearly, appropriate pharmacological studies of eliglustat in patients treated with amiodarone or quinidine should be done in future.

Amiodarone-induced reversible and irreversible hepatotoxicity: two case reports.

BACKGROUND: Amiodarone is a highly effective treatment for supraventricular and ventricular tachyarrhythmia; however, it could be associated with several serious adverse effects, including liver injury. CASE PRESENTATION: We report the clinical and histological features of two contrasting Japanese patients with amiodarone-induced reversible and irreversible hepatotoxicity. One patient with amiodarone-induced irreversible hepatotoxicity showed liver cirrhosis during treatment with amiodarone and died of hepatic failure; the other patient, who had reversible hepatotoxicity, showed a reversible course of liver function and imaging after discontinuation of amiodarone. CONCLUSIONS: We emphasize the importance of close monitoring of liver enzymes and evaluation of liver computed tomographic imaging as well as liver biopsy during treatment with amiodarone, and discontinuation should be considered when amiodarone-induced hepatotoxicity is suspected.

Identification and characterization of amiodarone metabolites in rats using UPLC-ESI-QTOFMS-based untargeted metabolomics approach.

Amiodarone is a class III anti-arrhythmic benzofuran derivative extensively utilized in treatment of life-threatening ventricular and supraventricular arrhythmias. However, amiodarone also produces adverse side effects including liver injury due to its metabolites rather than parent drug. The purpose of the present study was to identify metabolites of amiodarone in the plasma and urine of rats administered the drug by using an untargeted metabolomics approach. Drug metabolites were profiled by ultra-performance liquid chromatography-linked electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) and results subjected to multivariate data analysis. A total of 49 amiodarone metabolites were identified and their structures were characterized by tandem mass spectrometry. Amiodarone metabolites are presumed to be generated via five major types of metabolic reactions including N-desethylation, hydroxylation, carboxylation (oxo/hydroxylation), de-iodination, and glucuronidation. Data demonstrated that an untargeted metabolomics approach appeared to be a reliable tool for identifying unknown metabolites in a complex biological matrix.

Association between Serum Amiodarone and N-Desethylamiodarone Concentrations and Development of Thyroid Dysfunction.

OBJECTIVE: This retrospective cohort study was performed to examine the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and the development of thyroid dysfunction. METHODS: Patients treated with AMD from January 2012 to April 2016 were identified from the computerized hospital information system database at the National Cerebral and Cardiovascular Center. Only patients whose serum AMD and DEA concentrations had been determined at least once were included in the study. RESULTS: A total of 377 patients were enrolled. Consequently, 54 (14.3%) and 60 (15.9%) patients who developed AMD-induced thyrotoxicosis and hypothyroidism were included. The mean DEA/AMD ratio during the pre-index period in the thyrotoxicosis group (0.86 ± 0.24) was significantly higher than in the hypothyroidism (0.68 ± 0.27) and euthyroidism (0.78 ± 0.30; p < 0.0001) groups. In addition, the mean DEA/AMD ratio during the post-index period in the thyrotoxicosis group (1.05 ± 0.40) was significantly higher than in the hypothyroidism (0.81 ± 0.24) and euthyroidism (0.88 ± 0.22; p < 0.0001) groups. A persistently higher DEA/AMD ratio was observed throughout the study period in the thyrotoxicosis group. In addition, good correlations between the DEA/AMD ratio and the levels of free thyroxine, free triiodothyronine levels, and log (thyroid-stimulating hormone) were observed in the thyrotoxicosis and euthyroidism groups. CONCLUSION: Patients with AMD-induced thyrotoxicosis had an increased DEA/AMD ratio and patients with AMD-induced hypothyroidism had a decreased DEA/AMD ratio before the development of thyroid dysfunction. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction.

Association between N-desethylamiodarone/amiodarone ratio and amiodarone-induced thyroid dysfunction.

PURPOSE: We used a retrospective data mining approach to explore the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and thyroid-related hormone levels. METHODS: Laboratory data sets from January 2012 to April 2016 were extracted from the computerized hospital information system database at the National Cerebral and Cardiovascular Center (NCVC). Data sets that contained serum AMD and DEA concentrations and thyroid function tests, including thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were analyzed. RESULTS: A total of 1831 clinical laboratory data sets from 330 patients were analyzed. Data sets were classified into five groups (euthyroidism, hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, and subclinical hypothyroidism) based on the definition of thyroid function in our hospital. Most abnormal levels of thyroid hormones were observed within the therapeutic range of serum AMD and DEA concentrations. The mean DEA/AMD ratio in the hyperthyroidism group was significantly higher than that in the euthyroidism group (0.95 ± 0.42 vs. 0.87 ± 0.28, p = 0.0209), and the mean DEA/AMD ratio in the hypothyroidism group was significantly lower than that in the euthyroidism group (0.77 ± 0.26 vs. 0.87 ± 0.28, p = 0.0038). The suppressed TSH group (0.98 ± 0.41 vs. 0.87 ± 0.28, p < 0.001) and the elevated FT4 level group (0.90 ± 0.33 vs. 0.84 ± 0.27, p = 0.0037) showed significantly higher DEA/AMD ratios compared with normal level groups. The elevated TSH group showed a significantly lower DEA/AMD ratio compared with the normal group (0.81 ± 0.25 vs. 0.87 ± 0.28, p < 0.0001). CONCLUSIONS: High and low DEA/AMD ratios were associated with AMD-induced hyperthyroidism and hypothyroidism, respectively. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction.

Effect of Lactobacillus casei on the Pharmacokinetics of Amiodarone in Male Wistar Rats.

BACKGROUND AND OBJECTIVES: The probiotic bacterium Escherichia coli strain Nissle 1917 has previously been shown to alter the pharmacokinetics of amiodarone. The aim of this study was to determine whether the probiotic bacterium Lactobacillus casei produces similar alterations in amiodarone disposition. METHODS: A suspension of live probiotic bacteria L. casei strain DN-114 001 (1.5 × 109 CFU/dose; probiotic pre-treated group) or a saline solution (control group) was administered directly into the stomach of male Wistar rats (N = 30 in each group) by oral gavage daily for 7 consecutive days. On the eighth day, all rats (N = 60) were given a single oral dose of an amiodarone hydrochloride suspension (model drug; 50 mg/kg). The concentrations of amiodarone and of its main metabolite N-desethylamiodarone were determined in rat plasma by high-performance liquid chromatography. RESULTS: Comparison of the pharmacokinetics of amiodarone in the control group and probiotic pre-treated group revealed that the peak plasma concentration of amiodarone was delayed by >2 h in the probiotic pre-treated group. The plasma level of N-desethylamiodarone was unchanged in the probiotic pre-medicated group and its pharmacokinetic parameters were not altered. CONCLUSIONS: The slower absorption of amiodarone in the probiotic pre-treated rats compared to the control ones and the unchanged pharmacokinetics of its main metabolite suggest that the probiotic strain of L. casei DN-114 001 has probably no clinical consequences as the difference was not statistically significant.

Bioanalytical Method Validation for Dronedarone and Duloxetine in Blood Serum.

The present work relates to the development and validation of reversed-phase HPLC-UV-photodiode array methods for the estimation of two drugs in blood serum: dronedarone hydrochloride (DDN), a class III antiarrhythmic drug, and duloxetine hydrochloride (DLX), an antidepressant. Chromatographic analysis of DLX was carried out on a Nucleodur C18 column (250 × 4.6 mm, 5 µm) using ammonium acetate buffer (32 mM, pH 5.5) and acetonitrile (40 + 60, v/v; flow rate of 1.0 mL/min; detection wavelength of 290 nm) as the mobile phase. A Waters XTerra C18 column (250 × 4.6 mm, 5 µm) was used for the chromatographic analysis of DDN using an acetonitrile-ammonium formate buffer (20 mM, pH 3.0, with formic acid; 45 + 55, v/v; flow rate 1.0 mL/min) as the mobile phase. Pentazocine and bupropion HCl were used as the internal reference standards for DLX and DDN, respectively. Excellent linearity was observed for DLX (r2 = 0.9996; concentration range 0.2-10.0 µg/mL) and DDN (r2 = 0.9997; concn. range 2.0-50.0 µg/mL). The LODs for DLX and DDN were 0.022 and 0.78 µg/mL, respectively, and the LOQs 0.066 and 2.4 µg/mL, respectively.

The pharmacokinetics of dronedarone in normolipidemic and hyperlipidemic rats.

The objectives of the current study were to characterize the pharmacokinetic profile of dronedarone in the rat, and to examine the effect of hyperlipidemia on its pharmacokinetics. Single doses of dronedarone were administered to rats intravenously (4 mg/kg), orally (55 mg/kg) and intraperitoneally (65 mg/kg). To induce hyperlipidemia, some of the rats were administered intraperitoneal doses of poloxamer 407 before giving an oral dose of dronedarone. After intravenous doses of 4 mg/kg dronedarone, plasma clearance and volume of distribution at steady-state were 25.1 ± 8.09 mL/min/kg and 10.8 ± 4.77 L/kg, respectively. After oral doses the maximum plasma concentrations (Cmax) and their median time of attainment (tmax) were 1.87 ± 1.65 mg/mL and 3.5 h, respectively. Intraperitoneal administration of 65 mg/kg dronedarone base yielded plasma Cmax and median tmax of 0.816 ± 0.611 mg/mL and 3 h, respectively. Protein binding was high in NL and HL plasma. Dronedarone is extensively distributed with high volume of distribution in the rat. The drug showed poor bioavailability (<20%) after oral and intraperitoneal administration. The increased plasma concentrations after oral dosing to hyperlipidemic rats appears to be attributable to a direct effect on metabolizing enzymes or transport proteins. Copyright © 2016 John Wiley & Sons, Ltd.

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

OBJECTIVE: Postoperative 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. METHODS: After 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. RESULTS: The 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). CONCLUSIONS: Epicardial 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.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Quantitation of Flecainide, Mexiletine, Propafenone, and Amiodarone in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Flecainide, mexiletine, propafenone, and amiodarone are antiarrhythmic drugs that are used primarily in the treatment of cardiac arrhythmias. The monitoring of the use of these drugs has applications in therapeutic drug monitoring and overdose situations. LC-MS/MS is used to analyze plasma/serum extracts with loxapine as the internal standard to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix matched calibration curve is used for quantitation.

Reduced Food-Effect on Intestinal Absorption of Dronedarone by Self-microemulsifying Drug Delivery System (SMEDDS).

The oral absorption of dronedarone (DRN), a benzofuran derivative with anti-arrhythmic activity, is significantly affected by food intake. The absolute bioavailability of the marketed product (Multaq, Sanofi, U.S.) was about 4% without food, but increased to 15% when administered with a high fat meal. Therefore, to reduce the food-effect on the intestinal absorption of DRN, a novel self-microemulsifying drug delivery system (SMEDDS) was formulated and the comparative in vivo absorption studies with the marketed product were carried out using male beagle dogs either in the fasted or fed state. The SMEDDS consisted of the drug, Labrafil M 1944CS, and Kolliphor EL in a weight ratio of 1 : 1 : 2, rapidly formed a fine oil-in-water emulsion with a droplet size less than 50 nm. An in vivo absorption study revealed that the area-under-curve (AUC0-24 h) and maximal plasma concentration (Cmax) were 10.4-fold (p<0.05) and 8.6-fold (p<0.05) higher, respectively, after the marketed product was orally administered to beagles in the fed state when compared to those in the fasted state. This food-effect were remarkably alleviated by SMEDDS formulation, with AUC0-24 h and Cmax 2.9-fold (p<0.05) and 2.6-fold (p<0.05) higher in the fed state when compared to the fasted state, by facilitating intestinal absorption of DRN in the fasted state. The results of this study suggest that SMEDDS may decrease the differences in oral absorption of DRN between the prandial states, improving therapeutic efficacy as well as patient compliance.

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.

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.

Herb-drug pharmacokinetic interaction between carica papaya extract and amiodarone in rats.

PURPOSE: Carica papaya has been traditionally used worldwide in folk medicine to treat a wide range of ailments in humans, including the management of obesity and digestive disorders. However, scientific information about its potential to interact with conventional drugs is lacking. Thus, this work aimed to investigate the interference of a standardized C. papaya extract (GMP certificate) on the systemic exposure to amiodarone (a narrow therapeutic index drug) in rats. METHODS: In the first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. papaya (1230 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in the second study, rats were pre-treated for 14 days with C. papaya (1230 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the herbal extract vehicle. Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h following amiodarone administration; in addition, at 24 h post-dose, blood and tissues (heart, liver, kidneys and lungs) were also harvested. Thereafter, the concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were determined in plasma and tissue samples employing a high-performance liquid chromatography-diode array detection method previously developed and validated. RESULTS: In both studies was observed a delay in attaining the maximum plasma concentrations of amiodarone (tmax) in the rats treated with the extract. Nevertheless, it must be highlighted the marked increase (60-70%) of the extent of amiodarone systemic exposure (as assessed by AUC0-t and AUC0-∞) in the rats pre-treated with C. papaya comparatively with the control (vehicle) group. CONCLUSIONS: The results herein found suggest an herb-drug interaction between C. papaya extract and amiodarone, which clearly increase the drug bioavailability. To reliably assess the clinical impact of these findings appropriate human studies should be conducted.

Pharmacokinetics of dronedarone in rat using a newly developed high-performance liquid chromatographic assay method.

A sensitive and selective high-performance liquid chromatographic method for the determination of dronedarone in rat plasma was developed. Dronedarone was extracted using one-step liquid-liquid extraction. The separation of dronedarone was accomplished using a C18 analytical column. The mobile phase was composed of a combination of monobasic potassium phosphate and acetonitrile. The UV detection was at 254 nm for ethopropazine, the internal standard, and after its elution, changed to 290 nm for dronedarone detection. The total analytical run time was 20 min. Mean recovery was >80%; the assay had excellent linear relationships (>0.999) between peak height ratios and plasma concentrations; the lower limit of quantification 25 was ng/mL, based on 100 µL of rat plasma. Accuracy and precision were <18% over the concentration range of 25-500 ng/mL. The assay was applied successfully to the measurement of dronedarone plasma concentrations in rats given the drug orally.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Metabolite identification studies on amiodarone in in vitro (rat liver microsomes, rat and human liver S9 fractions) and in vivo (rat feces, urine, plasma) matrices by using liquid chromatography with high-resolution mass spectrometry and multiple-stage mass spectrometry: characterization of the diquinone metabolite supposedly responsible for the drug's hepatotoxicity.

RATIONALE: Several mechanisms have been anticipated for the toxicity of amiodarone, such as oxidative stress, lipid peroxidation, phospholipidosis, free radical generation, etc. Amiodarone is structurally similar to benzbromarone, an uricosuric agent, which was withdrawn from European markets due to its idiosyncratic hepatotoxicity. A proposed reason behind the toxicity of benzbromarone was the production of a reactive ortho-diquinone metabolite, which was found to form adducts with glutathione. Therefore, taking a clue that a similar diquinone metabolite of amiodarone may be the reason for its hepatotoxicity, metabolite identification studies were carried out on the drug using liquid chromatography/mass spectrometry (LC/MS) tools. METHODS: The studies involved in vitro (rat liver microsomes, rat liver S9 fraction, human liver S9 fraction) and in vivo (rat feces, urine, plasma) models, wherein the samples were analyzed by employing LC/HRMS, LC/MS(n) and HDE-MS. RESULTS AND CONCLUSIONS: A total of 26 metabolites of amiodarone were detected in the investigated in vitro and in vivo matrices. The suspected ortho-diquinone metabolite was one of them. The formation of the same might be an added reason for the hepatotoxicity shown by the drug.