Metabolism and pharmacokinetics of metaclazepam (Talis®), Part III: Determination of the chemical structure of metabolites in dogs, rabbits and men
| Autor: | H. Zeugner, F. Borchers, H. J. Hausleiter, G. Achtert |
|---|---|
| Rok vydání: | 1984 |
| Předmět: |
Adult
Male Metabolite Chemical structure Anxiolytic drug Pharmacology Mass Spectrometry Part iii Benzodiazepines chemistry.chemical_compound Dogs Species Specificity Pharmacokinetics medicine Animals Humans Pharmacology (medical) Biotransformation Chromatography High Pressure Liquid Hydrolysis Human physiology Metabolism Kinetics Anti-Anxiety Agents chemistry Dealkylation Solvents Metaclazepam Female Chromatography Thin Layer Rabbits medicine.drug |
| Zdroj: | European Journal of Drug Metabolism and Pharmacokinetics. 9:325-346 |
| ISSN: | 2107-0180 0378-7966 |
| DOI: | 10.1007/bf03189684 |
| Popis: | The metabolism of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2, 3-dihydro-1H-1,4-benzodiazepine (metaclazepam, Talis) in animals and men is described. Based upon mass spectrometry fifteen metabolites could be identified. Qualitative and quantitative differences in the biotransformation products of metaclazepam in comparison with the well known metabolites of other drugs in the 1,4-benzodiazepine class could be demonstrated. Metabolites with a benzodiazepine-2-one structure representing the most characteristic feature of other 1,4-benzodiazepines and their metabolites, were found in trace amounts only. The major metabolic pathways of metaclazepam led via stepwise demethylation of the O-methyl and/or the N-methyl group to O-demethyl-metaclazepam (M 2), N-demethyl-metaclazepam (M 7) and bis-demethyl-metaclazepam (M 6). Further aromatic hydroxylation yielded the metabolite M 1. Two metabolites with amino-benzophenone structure (M 5, M 8) which are in general known to result from other 1,4-benzodiazepines could be detected. Additionally a 3-oxo-benzodiazepine (M 4) was found. Minor biotransformation pathways led to a chlorophenyl-bromo-benzodiazepine (M 9) by loss of the side chain from bis-demethyl-metaclazepam and N-demethyl-metaclazepam. By further oxidation and degradation the 2-oxo-benzodiazepine M 10 and the dihydro-quinazoline M 12 were formed. The respective N-methylated metabolites M 13 and M 16 were possibly generated by the same pathway. Still open is the formation of M 15, a 1-methyl-3-hydroxy-4-(2'-chlorophenyl)-6-bromo-1,2-dihydroquinoline and M 11, a 2-methyl-4-(2'-chlorophenyl)-6-bromo-quinazoline. The substitution of bromine by a hydroxyl group during the formation of M 14 can be explained by a NIH-shift mechanism. Quantitative investigations show that the methoxymethyl side chain in the benzodiazepine ring system of metaclazepam acts as an effective barrier with respect to the metabolic attack at position two. We assume that this barrier only can be overcome by complete side chain degradation. This multi-step reaction can hardly compete with more favourable and faster conjugation and elimination processes. |
| Databáze: | OpenAIRE |
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