RESUMEN
A specific and highly sensitive method for the measurement of trazodone in plasma and brain of rat is presented. The compound and the internal standard were extracted from alkalinized samples with hexane and analysed by capillary gas chromatography with nitrogen-selective detection. The method was demonstrated to be accurate and precise. The limits of determination were 2 ng/ml for plasma and 24 ng/g for brain, which makes this procedure suitable for pharmacokinetic analysis.
Asunto(s)
Química Encefálica , Cromatografía de Gases/métodos , Trazodona/análisis , Trazodona/sangre , Animales , Masculino , Nitrógeno , Ratas , Ratas EndogámicasRESUMEN
The biotransformation of 6-benzoyl benzoxazolinone (6-BB), a non-narcotic peripheral analgesic, was studied in eight healthy volunteers after oral administration of a single dose of 1 g. Urinary metabolites were extracted either with ethyl acetate at different pH values or by percolating at pH 5 through Amberlite XAD 2 ion-exchange resin. Eluates were concentrated under vacuum, purified by thin-layer chromatography and analysed by gas chromatography/mass spectrometry or direct insertion probe mass spectrometry. Metabolites were identified with reference to the mass spectra of various synthesized compounds assumed to be metabolites of 6-BB, as N-methylated or monohydroxylated compounds. Another metabolic pathway was cleavage of the benzoxazolinone heterocycle giving 2-amino-5-benzoyl phenol after hydrolysis and decarboxylation. N-methyl, N-acetyl and hydroxylated metabolites having an amino-5-benzoyl phenol structure were also found.
Asunto(s)
Analgésicos/orina , Benzoxazoles , Oxazoles/orina , Oxazolidinonas , Adulto , Biotransformación , Cromatografía por Intercambio Iónico , Cromatografía en Capa Delgada , Cromatografía de Gases y Espectrometría de Masas , HumanosRESUMEN
Allopurinol, oxypurinol, hypoxanthine and xanthine were assayed simultaneously using a highly specific method combining gas chromatography and mass spectrometry. Two hypo-uricaemic prescriptions were compared: i) 300 mg of allopurinol (AL); and ii) 100 mg of allopurinol plus 20 mg of benzbromarone (AL + BZB). When administered acutely, their effects on blood uric acid levels were similar. Analysis of the pharmacokinetic parameters of allopurinol and its metabolite after each treatment showed dose-linearity for the metabolite but not for the drug itself. The area under the concentration time curve for allopurinol was 40.3 +/- 9.3 mumol l-1 h after AL, against 8.4 +/- 3.9 mumol-1 h after AL + BZB, while for oxypurinol it was 948.0 +/- 125.4 mumol l-1 h after AL and 285.2 +/- 77.9 mumol l-1 h after AL + BZB. The difference in dosage form may partly account for this difference, but the benzbromarone also seems to be involved. Its role on the blood uric acid lowering action of the drug association is complex. Although benzbromarone appreciably favors the elimination of oxypurinol, which should result in a weakening of its hypo-uricaemic action, this is offset by enhanced elimination of hypoxanthine and xanthine. Renal clearance of xanthine was significantly increased under AL + BZB (173.1 +/- 65.6 ml/min against 112.2 +/- 32.9 ml/min after AL). Similarly, blood xanthine levels were proportionately higher in the presence of benzbromarone. The action of the two agents may thus be synergistic and not antagonistic, a pharmacological justification for the therapeutic use of this drug association.
Asunto(s)
Alopurinol/farmacocinética , Benzbromarona/farmacocinética , Hipoxantinas/análisis , Oxipurinol/farmacocinética , Xantinas/análisis , Adulto , Combinación de Medicamentos , Cromatografía de Gases y Espectrometría de Masas , Semivida , Humanos , Hipoxantinas/sangre , Hipoxantinas/orina , Masculino , Modelos Biológicos , Xantinas/sangre , Xantinas/orinaRESUMEN
Plasma and blood xanthine and hypoxanthine levels were assayed using a sensitive and specific method involving gas chromatography-mass spectrometry, associated with an optimized sample preparation procedure. Physiological variation was studied in 224 subjects with no purine metabolism disorders. An age dependency for both compounds was found, comparable with that known for uric acid. The mean plasma levels for the 224 subjects were 0.65 +/- 0.24 microM for xanthine and 1.65 +/- 0.78 microM for hypoxanthine. Corresponding mean blood levels were 0.59 +/- 0.21 microM for xanthine and 1.72 +/- 0.74 microM for hypoxanthine. Plasma and blood levels were significantly different, by ca. 10%. Rapid in vitro release of hypoxanthine from erythrocytes and continuation of intraerythrocytal metabolism lead to overestimation exceeding 10% within half an hour after sample blood collection. Hence samples must be deproteinized promptly. Blood can therefore be conveniently used for oxypurine assay instead of plasma when prompt spinning of samples is difficult to manage, as is usually encountered in clinical practice.
Asunto(s)
Hipoxantinas/sangre , Xantinas/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Cromatografía de Gases y Espectrometría de Masas/métodos , Variación Genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Pharmacokinetic study of 458 L. via oral route, was performed in twelve normal volunteers, in a randomized crossover design of three galenic forms. Plasma concentrations were determined, after extraction, by HPLC, with spectrofluorimetric detection. Plasmatic kinetics were fitted to a bi-exponential function with a distribution half-life of 1h and an elimination half-life of 11.5 to 14.7 h according to the form. Pharmacokinetic parameters evaluated as area under the curve (AUC), maximum plasma concentrations (Cmax), relative bioavailability (F'), have shown strong interindividual differences, specially in women group, and this with tobacco smoking.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/farmacocinética , Isoquinolinas/farmacocinética , Tetrahidroisoquinolinas , Administración Oral , Adulto , Femenino , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/sangre , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/sangre , MasculinoRESUMEN
A capillary column gas chromatography--mass fragmentographic method for metapramine and its three major demethylated metabolites is described. Compounds are extracted from plasma using a double-extraction procedure and transformed into N-trifluoroacetyl derivatives. The detection is performed by monitoring specific ions for metapramine and for its metabolites with a mass detector. In spite of extensive metabolism in the liver and rapid elimination of metapramine, plasma concentrations of both metapramine and its metabolites can be simultaneously followed over 24 h after a single 150-mg oral dose, because of the sensitivity and selectivity of the method. This method has been successfully applied to the analysis of samples obtained from patients who were at steady state with metapramine and to a pharmacokinetic study in a healthy volunteer.
Asunto(s)
Dibenzazepinas/sangre , Biotransformación , Remoción de Radical Alquila , Dibenzazepinas/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Humanos , CinéticaRESUMEN
The differential assay of xanthine and hypoxanthine in plasma, serum and erythrocytes was performed using a combination of GC and MS with chemical ionisation. The influence of sampling conditions was studied, in particular the latency period between the collection of the blood and the separation of the plasma and the cells, the nature of the anticoagulant used and the method of storage of the samples. Firstly, this study confirms that EDTA is the most appropriate anticoagulant. It also showed that an immediate deproteinisation is necessary after separation of the plasma and the cells, in order to prevent any "in vitro" modification of the oxypurines, in particular erythrocyte hypoxanthine.