RESUMO
A simple, rapid, selective, and sensitive analytical method was developed for the quantification of atenolol in small volumes of plasma, by high-performance liquid chromatography with fluorescence detection. Only 200 microL of plasma was used for chromatographic analysis. Separation was performed on a C18 reverse-phase column (4 microm) using a binary mobile phase consisting of 0.05 M of phosphate buffer, pH 5.5, and methanol (80:20, vol/vol) at a flow rate of 0.7 mL/minute. The retention times of atenolol and of the internal standard (sotalol) were 12.7 and 10.4 minutes, respectively. Validation of this analytical method showed a good linear correlation (8-2000 ng/mL), high sensitivity (quantification limit: 8 ng/ml and detection limit: 4 ng/mL), accuracy of 99.3%, and intraday and interday precision of 5.3% and 6.9%, respectively. Absolute recovery was 93.7%. The method was found to be robust, with acceptable stability. The analytical method was validated by the quantification of atenolol in plasma obtained from 2 patients with unstable angina, scheduled for myocardium revascularization surgery, who were chronically treated with 50 mg of atenolol administered per os once a day. The method developed was found to be adequate for use in pharmacokinetic studies and in adjusted dose pharmacotherapy.
Assuntos
Atenolol/sangue , Cromatografia Líquida de Alta Pressão/métodos , Fluorescência , Microquímica/métodos , Administração Oral , Antagonistas Adrenérgicos beta/sangue , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso de 80 Anos ou mais , Angina Instável/sangue , Angina Instável/tratamento farmacológico , Angina Instável/cirurgia , Atenolol/farmacocinética , Atenolol/uso terapêutico , Monitoramento de Medicamentos/métodos , Estabilidade de Medicamentos , Humanos , Microquímica/economia , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sotalol/sangue , Sotalol/farmacocinética , Sotalol/uso terapêutico , Temperatura , Fatores de TempoRESUMO
A simplified high performance chromatographic method (HPLC) was performed for sotalol enantiomers in plasma samples for purposes of investigation of the kinetic disposition of racemic sotalol in cardiac arrhythmic patients under multiple dose and multidrug therapy regimens. After addition of NaCl:Na2CO3 (4:1) and plasma protein precipitation by acetonitrile:methanol mixture (1:1) the supernatant was evaporated. The residue containing sotalol racemate was submitted to derivatization reaction with (-)-menthylcloroformate to R(-)- and S(+)-sotalol diastereoisomers. The diastereoisomers were resolved in HPLC, by a C18 column with fluorescent detection under lexcitation = 235 nm and lemission = 310 nm. The retention times for R- and S-sotalol were 20 and 22 minutes while that of internal standard S(-)-atenolol, was 17 minutes. The detection limit for each enantiomer was 12.5 ng/mL and intra-day/inter-day coefficients of variation were less than 10% for each enantiomer within a concentration range of 200 and 2000 ng/mL. The method was appropriate for the objective proposed.
Assuntos
Antagonistas Adrenérgicos beta/sangue , Sotalol/sangue , Antagonistas Adrenérgicos beta/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Sotalol/farmacocinética , Espectrometria de Fluorescência , EstereoisomerismoRESUMO
R,S-sotalol, a ss-blocker drug with class III antiarrhythmic properties, is prescribed to patients with ventricular, atrial and supraventricular arrhythmias. A simple and sensitive method based on HPLC-fluorescence is described for the quantification of R,S-sotalol racemate in 500 microl of plasma. R,S-sotalol and its internal standard (atenolol) were eluted after 5.9 and 8.5 min, respectively, from a 4-micron C18 reverse-phase column using a mobile phase consisting of 80 mM KH2PO4, pH 4.6, and acetonitrile (95:5, v/v) at a flow rate of 0.5 ml/min with detection at lambdaex = 235 nm and lambdaem = 310 nm, respectively. This method, validated on the basis of R,S-sotalol measurements in spiked blank plasma, presented 20 ng/ml sensitivity, 20-10,000 ng/ml linearity, and 2.9 and 4.8% intra- and interassay precision, respectively. Plasma sotalol concentrations were determined by applying this method to investigate five high-risk patients with atrial fibrillation admitted to the Emergency Service of the Medical School Hospital, who received sotalol, 160 mg po, as loading dose. Blood samples were collected from a peripheral vein at zero, 0.5, 1.0, 1.5, 2.0, 3.0, 4. 0, 6.0, 8.0, 12.0 and 24.0 h after drug administration. A two-compartment open model was applied. Data obtained, expressed as mean, were: C MAX = 1230 ng/ml, T MAX = 1.8 h, AUC T = 10645 ng h-1 ml-1, Kab = 1.23 h-1, alpha = 0.95 h-1, ss = 0.09 h-1, t((1/2))ss = 7.8 h, ClT/F = 3.94 ml min-1 kg-1, and Vd/F = 2.53 l/kg. A good systemic availability and a fast absorption were obtained. Drug distribution was reduced to the same extent in terms of total body clearance when patients and healthy volunteers were compared, and consequently elimination half-life remained unchanged. Thus, the method described in the present study is useful for therapeutic drug monitoring purposes, pharmacokinetic investigation and pharmacokinetic-pharmacodynamic sotalol studies in patients with tachyarrhythmias.
Assuntos
Antiarrítmicos/sangue , Fibrilação Atrial/sangue , Cromatografia Líquida de Alta Pressão/métodos , Sotalol/sangue , Antiarrítmicos/farmacocinética , Antiarrítmicos/uso terapêutico , Área Sob a Curva , Fibrilação Atrial/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sotalol/farmacocinética , Sotalol/uso terapêuticoRESUMO
Estudou-se no presente trabalho a disposiçäo cinética dos enantiômeros do sotalol em 13 pacientes miocardiopatas crônicos portadores de taquiarritmias, utilizando método analítico em cromatografia líquida de alta eficiência com detector de fluorescência, após derivatizaçäo do fármaco para resoluçäo dos isômeros R(-)- e S(+)-sotalol. Os pacientes estavam sob regime de dose múltipla de 320 mg/dia p.o. de cloridrato de sotalol. Após coleta seriada de sangue, a disposiçäo cinética do R,S-sotalol foi avaliada aplicando-se modelo monocompartimental aberto. Obtiveram-se os seguintes valores, para R,S-, R(-)- e S(+)-sotalol, para os parâmetros cinéticos relativos às fases de absorçäo, (expressos através de Média ñ DP): 'K IND. ab (1,081 ñ 0,134, 1,06 ñ 0,18, 1,17 ñ 0,17 h-û); disponibilidade sistêmica, 'AUC IND.T POT.SS' (14386,9 ñ 1308,2, 6959,3 ñ 597, 7387,3 ñ 711 ng.h/mL), 'C POT.SS IND.MAX'(2046,4 ñ 179,3, 1006,6 ñ 87, 1040,0 ñ 94,2ng/mL), ...