RESUMEN
Two capillary electrophoretic (CE) methods for the determination of conjugated metabolites of the antihistaminic drug dimethindene were developed. These methods allow the determination of the diastereomeric ratios of both Phase II glucuronides, 6-hydroxy dimethindene glucuronide (5) and 6-hydroxy-N-demethyl dimethindene glucuronide (6). Furthermore, after enzymatic deconjugation of both glucuronides, enantiomeric ratios of the hydroxylated Phase I metabolites 3 and 4 were determined. For comparison, glucuronides 5 and 6 were prepared by enzymatic synthesis and identified by MALDI-TOF mass spectrometry and deconjugation with beta-glucuronidase to the corresponding phenols 3 and 4. The assay of the glucuronides in rat urine and serum was performed by a combination of liquid/liquid extraction followed by solid phase extraction. After a high dose treatment with racemic dimethindene the diastereomeric glucuronides 5 and 6 could be directly determined in the urine of a guinea pig by CE without prior extraction or preconcentration of the urine sample. In all cases, stereoselectivities of the formation of Phase I as well as Phase II metabolites were observed.
Asunto(s)
Dimetindeno/sangre , Electroforesis Capilar/métodos , Antagonistas de los Receptores Histamínicos H1/sangre , Animales , Dimetindeno/análogos & derivados , Glucuronidasa/metabolismo , Glucurónidos/sangre , Cobayas , Humanos , Conformación Molecular , Estructura Molecular , Ratas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
A gas chromatographic-mass fragmentographic method using ammonia chemical ionization for the determination of dimethindene in human plasma is described. The drug was isolated from plasma by liquid-liquid extraction with hexane-2-methylbutanol. Plasma components were separated on a capillary column coated with chemically bonded methyl silicone. For detection of dimethindene, its quasi-molecular ion (M + H+) was mass fragmentographically monitored after chemical ionization with ammonia as reagent gas. Dimethindene was quantified using methaqualone as the internal standard: the quantification limit in plasma was 0.2 ng/ml, the within-run precision was 8.0% and the inter-run precision 5.6%. The plasma concentration-time profile was established after a single dose of 4 mg of dimethindene with an average maximum concentration of 5.5 ng/ml, detectable up to 48 h post application.
Asunto(s)
Dimetindeno/sangre , Cromatografía de Gases y Espectrometría de Masas/métodos , Amoníaco/química , Humanos , Iones , Metacualona/sangre , Control de Calidad , Estándares de ReferenciaRESUMEN
Dimethindene, an antihistaminic drug, is the treatment of choice in dialysis patients suffering from skin itching. During hemodialysis procedures not only toxic metabolites, but also drugs are extracted from plasma. To answer the question if dimethindene is dialyzable from plasma, three healthy male volunteers received 4 mg of dimethindene solution intravenously. Ten minutes later 100 ml cubital vein blood was taken and 25,000 I.E. Liquemine was added. Plasma was separated and pumped through a cuprophan hollow fiber dialyzing module with an effective surface of 35 cm2. In periods of ten minutes samples of plasma and dialysate were taken to analyze their dimetindene concentrations. A mean clearance of 38 ml/min*m2, SD 10.2 and coefficient of variation [%] 26.8 was found. This is comparable to the well known clearance of theophylline, so it can be considered that dimethindene is eliminated from plasma during hemodialysis procedures.
Asunto(s)
Dimetindeno/sangre , Algoritmos , Dimetindeno/administración & dosificación , Humanos , Inyecciones Intravenosas , Masculino , Diálisis RenalRESUMEN
Dimethindene maleate is a well known H1-receptor antagonist with strong affinity to the H1-receptor. In order to evaluate the time course of its activity, dimethindene maleate was investigated in a histamine provocation model in man. Eight healthy male volunteers were treated either with 4 mg dimethindene maleate using a commercially available solution (Fenistile, Tropfen) or an identically appearing placebo solution (po) following a double-blind, crossover study design. Intracutaneous histamine injections were administered at -1, 2, 5, 14, 17, 20, 23, 26 and 29 h following drug administration. Areas of flares and weals were measured 5, 10, 20, and 30 min following histamine provocation. A strong inhibition of the development of flares and weals was observed to be more pronounced in flares than in weals. Baseline adjusted areas under the curve differ statistically significantly following verum and placebo treatment conditions (P = 0.0028). According to the time schedule of the study maximal effects were observed at time point 5 h. The mean residence times of the inhibitory effects were calculated to be congruent to 13 h compared to the mean residence times of dimethindene blood levels of approximately 8 h indicating a non-linear relationship between blood level and effect.
Asunto(s)
Dimetindeno/farmacocinética , Antagonistas de los Receptores Histamínicos/farmacocinética , Administración Oral , Adulto , Dimetindeno/sangre , Dimetindeno/farmacología , Método Doble Ciego , Semivida , Histamina/administración & dosificación , Antagonistas de los Receptores Histamínicos/sangre , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Hidrocortisona/sangre , Masculino , Distribución AleatoriaRESUMEN
A simple method for the determination of dimethindene down to a concentration of 10 ng/ml in human urine and serum is described. After the addition of an internal standard, the dimethindene is extracted as the free base with pentane. Measurements are made directly by gas--liquid chromatography using a flame ionization detector.