RESUMO
Antecedentes: Amiodarona (A) es la droga antiarrítmica más utilizada en la actualidad. No obstante, algunos aspectos de su compleja farmacología son todavía poco conocidos en ciertos grupos de pacientes. Objetivo: Estudiar los parámetros farmacocinéticos de A después de una alta dosis de carga oral en pacientes (P) sometidos a cirugía coronaria. Métodos: Cuarenta y tres P sometidos a cirugía coronaria recibieron una dosis oral de 30 mg/kg en dosis fraccionada como tratamiento profiláctico de arritmias en el post operatorio. Las concentraciones sanguíneas de la droga fueron medidas a tiempos sucesivos, por HPLC, hasta las 96 h de su administración. En base a la curva obtenida de concentración sanguínea vs tiempo, los parámetros farmacocinéticos fueron calculados mediante un programa computacional independiente del modelo compartimental. Resultados: La concentración sanguínea de A alcanzó un valor máximo de 2,3 +/- 1,5µg/ml a las 10 h de la administración de la droga. Posteriormente, se observó un descenso gradual con un valor de 0,4 +/- 0,1 µg/ml a las 96h de administración. Los parámetros farmacocinéticos obtenidos fueron: Vida media 29,1 +/- 11,3h; Area bajo la curva 096 63,6 +/- 22,3 (µg/ml)h; Clearance total 6,1 +/- 2,2 ml/min/kg; Volumen de distribución 15,6 +/- 5,4 L/kg. Conclusiones: La farmacocinética de A presenta diferencias con lo encontrado en estudios de dosis única en otros grupos de pacientes. El presente trabajo puede servir para esquemas de dosificación menos empíricos de A.
Background: Amiodarone is currently the most commonly used antiarrhythmic drug. However, some aspects of its complex pharmacokinetics in particular groups of patients are not well known. Aim: to study the pharmacokinetics of amiodarone after a high loading oral dose in patients undergoing coronary revascularization surgery. Methods: Forty three patients operated on for coronary artery disease received oral dose amiodarone, 30mg/Kg, in a fractioned dose as a prophylactic antiarrhythmic medication following surgery. Blood amiodarone concentration was measured at successive intervals for 96 hr. A software based on a non compartmental model was used to determine pharmacokinetic parameters. Results: Maximal blood concentration of amiodarone was 2.3 +/-1.5µg/ml 10hr after drug administration. A subsequent gradual decrease of amiodarone blood level was observed, down to 0.4 +/- 0.1µg/ml at 96hr post drug administration. The half-life time was 29.1 +/- 11.3hr. The area under de 0 to 96hr curve was 63.6 +/- 22.3µg/ml.Total clearance was 6.1 +/- 2.2 ml/min/kg. The distribution volume was 15.6 +/- 5,4 L/kg. Conclusion: Pharmacokinetics of amiodarone differs from that obtained following a single dose in other groups of patients. The data provided may be used to determine more objective amiodarone dosing schemes.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Amiodarona/farmacocinética , Coração , Administração Oral , Antiarrítmicos/farmacocinética , Amiodarona/administração & dosagem , Amiodarona/sangue , Procedimentos Cirúrgicos Cardíacos , Sistema de Condução Cardíaco , Fatores de TempoRESUMO
OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
Assuntos
Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Adulto , Amiodarona/sangue , Antiarrítmicos/sangue , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Cromatografia Líquida , Estudos Cross-Over , Feminino , Alimentos , Humanos , Absorção Intestinal , Masculino , Espectrometria de Massas por Ionização por Electrospray , Comprimidos , Espectrometria de Massas em TandemAssuntos
Humanos , Amiodarona/farmacologia , Frequência Cardíaca , Pressão Sanguínea , Administração Oral , Amiodarona/administração & dosagem , Amiodarona/efeitos adversos , Amiodarona/sangue , Arritmias Cardíacas/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Fatores de TempoRESUMO
Our aim was to develop a quantitative method for serum amiodarone measurement using high performance liquid chromatography with ultraviolet photometric detection. We studied previous reports in the literature in order to obtain a simpler method to be used routinely in our TDM unit. Sample preparation was based on protein precipitation adding 2 parts of acetonitrile to 1 part of serum, followed by vortex-agitation for 45 s, incubation at 24 degrees C for 5 min, and centrifugation at 6000 x g for 2 min. Twenty microliters of the supernatant was directly injected into the chromatographic system. A microBondapak CN RP column (3.9 x 150 mm) at 45 degrees C, with a mobile phase consisting of KH2PO4 10 mM/methanol/acetonitrile (40:37:23 v/v/v), pH 3.5, were used. Eluting with a flow rate of 0.6 mL/mm the retention time of amiodarone was approximately 4.9 min. Detection was performed at 242 nm and the quantification was made by peak height comparison with external standards. The mass/response ratio is linear (r2 > 0.99) within a mass range of 2.96 to 18,930 ng of injected amiodarone, which exceeds the requirements for the monitoring of serum levels (0.3 to 6.0 micrograms/mL). Sample storage should be done with acetonitrile-extracted sera at -16 degrees C to avoid degradation. The method is very efficient, linear, sensitive and specific but it also simpler and cheaper than others reported in the literature.
Assuntos
Amiodarona/sangue , Antiarrítmicos/sangue , Proteínas/química , Precipitação Química , Cromatografia Líquida de Alta Pressão/métodos , Custos e Análise de Custo , Humanos , Sensibilidade e EspecificidadeRESUMO
Nos propusimos desarrollar un método para la medición de amiodarona en suero mediante cromatografia líquida de alta resolución con detección ultravioleta, optimizando las condiciones analíticas descritas en la literatura y determinar las condiciones óptimas de almacenamiento de la muestra, para la instalación de un servicio nacional de referencia. la preparación de la muestra consistió en la adición de 2 partes de acetonitrilo a 1 parte de suero, agitación por 45s, incubación a 24§C por 5 min, centrifugación a 6000 x g durante 2 min e inyección de 20 mu L del sobrenadante al cromatógrafo. Utilizando una columna mu Bondapak CN RP (3.9 x 150 mm) a 45§C, con una fase móvil compuesta por KH2PO4 10 mM/metanol/acetonitrilo (40:37:223 v/v/v) a pH 3,5, bombeada a 0,6 mL/min, obtuvimos un tiempo de retención de 4,9 min. La detección se realizó a 242 nm, y la cuantificación mediante comparación con estándares externos; el límite de detección fue de 0,11 mu g/mL. La relación masa/respuesta fue lineal (r2 > 0,99) para inyecciones con masa nominal de 2,96 a 18930 ng, lo cual excede lo requerido para el monitoreo de amiodarona sérica (0,3 a 6,0 mu g/ml). La recuperación fue de 99,26 por ciento más o menos 2,84 por ciento. El almacenamiento a -16§C de muestras precipitadas evita la degradación de la droga. Este método resultó más eficiente, sencillo y económico que otros ya descritos, manteniendo la sensibilidad, especificidad y linealidad requeridas para ser considerado un método óptimo para la cuantificación de amiodarona en suero.
Assuntos
Humanos , Proteínas , Amiodarona/sangue , Antiarrítmicos/sangue , Precipitação Química , Cromatografia Líquida de Alta Pressão/métodos , Sensibilidade e Especificidade , Custos e Análise de Custo , Amiodarona/administração & dosagem , Amiodarona/farmacologia , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacologiaRESUMO
We measured plasma concentrations of amiodarone and desethylamiodarone by HPLC in 44 outpatients aged 24 to 67 years old (21 male), receiving the drug during at least three months. The drug was indicated for supraventricular arrhythmias in 37 patients and ventricular arrhythmias in seven. Plasma concentrations of amiodarone, desethylamiodarone and their ratio were 1.71 +/- 0.82, 0.85 +/- 0.42 micrograms/ml and 2.02 respectively, for a mean daily dose of 223 +/- 88 mg. In 41 patients, arrhytmias were successfully treated. These patients received a mean daily dose of 220 +/- 86 mg and concentrations of amiodarone, desethylamiodarone and their ratio were 1.75 +/- 0.86, 0.88 +/- 0.45 micrograms/ml and 1.99 respectively. In three patients with treatment failure, receiving a daily dose of 257 +/- 115 mg, these figures were 1.2 +/- 0.3, 0.5 +/- 0.1 micrograms/ml and 2.4 respectively. We conclude that our patients had lower plasma concentrations of desethylamiodarone and higher amiodarone/desethylamiodarone ratios than those reported in other countries.
Assuntos
Amiodarona/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Adulto , Idoso , Amiodarona/análogos & derivados , Amiodarona/sangue , Cromatografia Líquida de Alta Pressão , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We measured plasma concentrations of amiodarone and desethylamiodarone by HPLC in 44 outpatients aged 24 to 67 years old (21 male), receiving the drug during at least three months. The drug was indicated for supraventricular arrythmias in 37 patients and ventricular arrhytmias in seven. Plasma concentrations of amiodarone, desethylamiodarone and their ratio were 1.71ñ0.82, 0.85ñ0.42 µg/ml and 2.02 respectively, for a mean daily dose of 223ñ88 mg. In 41 patients, arrhytmias were succesfully treated. These patients received a mean daily dose of 220ñ86 mg and concentrations of amiodarone, desethylamiodarone and their ratio were 1.75ñ0.86, 088ñ0.45 µg/ml and 1.99 respectively. In 3 patients with treatment failure, receiving a daily dose of 257ñ115 mg, these figures were 1.2ñ0.3, 0.5ñ0.1 µg/ml and 2.4 respectively. We conclude that our patients had lower plasma concentrations of desethylamiodarone and higher amiodarone/desethylamiodarone ratios than those reported in other countries
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Arritmias Cardíacas/tratamento farmacológico , Amiodarona/farmacocinética , Amiodarona/sangue , Doença Crônica/tratamento farmacológicoRESUMO
A simple specific and sensitive high pressure liquid chromatography method (HPLC) to measure amiodarone and desethylamiodarone is described. The plasma sample is deproteinized with acetonitrile and a 50 ul aliquote run in the HPLC system with reverse phase column (C-18). Methanol-ammonium hydroxide is used to separate and spectrophotometric measurements are read at 254 nm.95% of the drug present in plasma is extracted with this method, with a sensitivity of 0.03 ug/ml and a day to day variation under 3%. Preliminary measurements were analyzed in 14 subjects receiving amiodarone for treatment of supraventricular arrhythmia. With a mean dose of 267 +/- 116 (SD) mg/day, plasma levels of 1.3 +/- 0.6 ug.ml for amiodarone and 0.9 +/- 0.5 mg/ml for desethylamiodarone were obtained.
Assuntos
Amiodarona/análogos & derivados , Amiodarona/sangue , Cromatografia Líquida de Alta Pressão , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations (68% to 800%) in the presence of preserved serum creatinine and BUN concentrations. Digoxin half-life was prolonged. Digoxin accumulation could be attributed in part to the decrease in the renal clearance of digoxin resulting from inhibited tubular secretion of the drug and to the reduction in the distribution volume of digoxin caused by amiodarone. Creatinine clearance was not affected by amiodarone. This interaction appears to be more acute in children than in adults, presumably because of the more important role of the renal tubular secretion of digoxin in children. Whenever digoxin and amiodarone therapy are combined, the digoxin serum concentration should be monitored carefully, with appropriate reduction of the digoxin dose.