RESUMEN
The metabolic fate of chlormethiazole in healthy male subjects has been investigated following the oral administration of a single dose of chlormethiazole edisylate. Five urinary C-oxidation metabolites were identified and shown to be identical with previously reported metabolites. A novel metabolite, of molecular formula C5H7NO2S, was shown by trimethylsilylation, deuterium exchange, reduction studies and by its i.r., n.m.r. and mass spectrum, to be 4,5-dimethylthiazole-N-oxide-S-oxide. This is the first reported metabolite which involves the oxidation of the two heterocyclic atoms in aromatic rings. The formation and thermal stability of the compound is ascribed to resonance stabilization.
Asunto(s)
Clormetiazol/metabolismo , Tiazoles/análisis , Fenómenos Químicos , Química , Clormetiazol/orina , Cromatografía de Gases , Deuterio , Humanos , Masculino , Espectrometría de Masas , Oxidación-Reducción , Titanio , Compuestos de TrimetilsililoRESUMEN
As the result of a renewed extensive investigation of clomethiazole (Distraneurin) metabolism five previously unknown metabolites could be isolated from human urine. Their structures were elucidated by mass spectrometry. Whereas previous investigations on the metabolism of clomethiazole had demonstrated changes only of the ethyl group, we now found metabolites attached to the methyl group, too. The newly isolated compounds 5-(1-hydroxy-2-chloroethyl)-4-methylthiazole (9) and 5-(2-hydroxyethyl)-4-thiazole carboxylic acid lactone (5) were found to be more abundant in human urine than 4-methyl-5-thiazole acetic acid previously considered as the main metabolite.
Asunto(s)
Clormetiazol/orina , Hipnóticos y Sedantes/orina , Biotransformación , Fenómenos Químicos , Química , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Hidrólisis , MasculinoRESUMEN
It may become necessary to prove that clomethiazole (Distraneurin) has been taken when supervising addicts, with traffic accidents under the influence of drugs and when the cause of death is unclear. Since the compound is almost completely metabolized in the body, a method has been developed to detect its main metabolite, 4-methyl-5-thiazole acetic acid in the urine. The acid can be precisely identified and determined by a combination of selective extractions, high-voltage electrophoresis and UV measurements.
Asunto(s)
Clormetiazol/orina , Medicina Legal , Clormetiazol/envenenamiento , Humanos , MétodosRESUMEN
A simple method has been developed whereby chlormethiazole, ethchlorvynol and trichloroethanol can be simultaneously detected and measured in biological fluids. The procedure is based upon the rapid extraction of a small (50-microliter) sample volume with an equal volume of chloroform containing an internal standard, followed by the gas-liquid chromatographic analysis of this extract. Specimens of blood plasma or serum, urine and gastric contents can be used, and no interference from either endogenous or exogenous sources has been observed. The method is suitable for the measurement of the plasma concentrations of these compounds attained after overdosage.
Asunto(s)
Clormetiazol/envenenamiento , Clorhidrinas/envenenamiento , Etclorvinol/envenenamiento , Clormetiazol/sangre , Clormetiazol/orina , Clorhidrinas/sangre , Clorhidrinas/orina , Cromatografía de Gases , Cromatografía Liquida , Etclorvinol/sangre , Etclorvinol/orina , Etilenclorhidrina/análogos & derivados , Humanos , Intoxicación/sangre , Intoxicación/orinaRESUMEN
1. Chlormethiazole and five of its metabolites excreted in urine in man have been investigated by g.l.c.-mass spectrometry. 2. Four metabolites have been identified by comparison with authentic compounds as 5-acetyl-4-methylthiazole, 5-(1-hydroxyethyl)-4-methylthiazole, 5-(2-hydroxyethyl)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid; 4-methyl-5-thiazoleacetaldehyde is proposed for the other metabolite. 3. The amounts of chlormethiazole and its identified metabolites excreted in urine have been quantitatively determined after a single oral dose in three healthy adults. Approximately 16% of the dose was excreted as chlormethiazole, 5-acetyl-4-methylthiazole, 5-(1-hydroxyethyx)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid.