Metabolism and pharmacokinetics of metaclazepam (Talis®), Part III: Determination of the chemical structure of metabolites in dogs, rabbits and men

Abstract

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.

Characterization and differentiation of heterocyclic isomers. Part 2. Mass spectrometry and molecular orbital calculations on pyrrolo[1,2-a][1,4]benzodiazepin-4-one, -6-one, and -4,6-dione

“…Because of its high sensitivity and specificity, mass spectrometry has been used widely to characterize several 1,4and 1,5-benzodiazepine derivatives [5][6][7][8][9], as well as to elucidate their biotransformation pathways and pharmacokinetics [10,11]. Mass spectrometric characterization of fused benzodiazepines, such as imidazo- [12,13], pyrrolo- [14], s-triazolo-benzodiazepines [15], and dibenzodiazepines [16][17][18] also has been reported.…”

Screening and detection of the new 1,4-benzodiazepine derivative metaclazepam

“…Several important mass spectra have been et al [7]. GLC on a 165 cmx 2 mm OV-101 column and a 148 cm x 2 mm OV-17 column in a Varian Aerograph, Series 2100, instrument, with Gas Chrom Q as support and nitrogen as carrier gas, FID detection, oven temperature 250 ~ or 280 ~ and injection port and detector at 300 ~ gives the Kov~ts retention indices shown below.…”

“…The biotransformation of metaclazepam has been extensively studied by Borchers et al [7], who isolated and identified 15 metabolites. Fig.…”

“…Excretion is equally divided between the urine and the bile [7,8]. Its metabolic transformation soon begins, and leads to the three main metabolites (II, III, IV) which have the same pharmacological reaction characteristics as metaclazepam.…”