RESUMEN
The metabolic pathway of dimetindene (dimetindene maleate, Fenistil), an antiallergic drug commercially available for more than 20 years, has remained unknown. By means of HPLC, GC-MS and MS-MS, dimetindene was found to be hydroxylated on the indene moiety of the molecule both in vitro with hepatic microsomes of several species and in vivo in man. Cochromatographic analysis (HPLC and GC-MS) of the primary metabolites produced in vitro and in vivo demonstrated their similarities but revealed differences from the chemically synthesized 5-hydroxy-dimetindene. Using large volumes of in vitro incubations of rat microsomes with dimetindene and cofactors, 1.15 mg of pure primary metabolite were first produced and then extensively purified. The study of the NMR proton in one and two dimensions (COSY) clearly demonstrated that this metabolite is hydroxylated on the C6 of the indene moiety as compared to the C5 for the synthetic product.
Asunto(s)
Dimetindeno/metabolismo , Antagonistas de los Receptores Histamínicos H1/metabolismo , Adulto , Animales , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , Haplorrinos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Endogámicas , PorcinosRESUMEN
The effect of alcoholic cirrhosis of the liver on the disposition and metabolism of (+)-cyanidanol-3 has been studied in three patients. Following oral intake of U-14C-(+)-cyanidanol-3 2 g, the unchanged drug was detected in plasma between 0.5 and 24 h after dosing and the metabolites, measured only as 14C-levels, were still detectable at 120 h. A mean of 55% of the dose was excreted in the urine, in which the major metabolites were the glucuronic and sulphuric acid conjugates of (+)-cyanidanol-3 and 3'-O-methyl-(+)-cyanidanol-3, although one patient excreted a larger proportion as non-conjugated metabolites. The pattern of metabolism in the patients did not differ significantly from that in control subjects, suggesting that the drug is handled by the cirrhotic liver in a similar manner to the normal liver.
Asunto(s)
Catequina/farmacocinética , Cirrosis Hepática Alcohólica/metabolismo , Catequina/sangre , Catequina/orina , Eritrocitos/metabolismo , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana EdadRESUMEN
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.