Quantitative analysis of CM 6912 (ethyl loflazepate) and its metabolites in plasma and urine by chemical ionization gas chromatography mass spectrometry. Application to pharmacokinetic studies in man.
A chemical ionization gas chromatographic mass spectrometric assay is described for ethyl loflazepate (CM 6912), a new benzodiazepine with a potent anti-anxiety activity, and two of its metabolites in plasma and urine. The parent drug was separated from the biological samples by simple extraction at pH 9. In all samples analysed, parent drug levels were below the detection limit, confirming its extensive biotransformation at the sites of absorption and during its first pass through the liver. Pharmacokinetic data were obtained by measuring the total levels of two of the major metabolites. Accurate data may not be obtained for both metabolites separately since one of them (M1) is chemically transformed to metabolite M2 during plasma sampling, storage and extraction. Their total levels were measured after complete degradation of the unstable metabolite and extraction of the sample at pH 9. The precision and accuracy of this method are better than 10% in the low ng range. The detection limit is 1 ng ml-1. Pharmacokinetic data were obtained from human volunteers given a single oral dose of 2 mg CM 6912 in tablet form. Cp max values ranged from 30 to 55 ng ml-1 and were reached within 1.5 to 3 h after administration. Following the achievement of peak levels the concentration declined with an apparent biexponential pattern showing an elimination half-life ranging from 51 to 103 hours in its terminal phase.
D000328:Adult; D000818:Animals; D014151:Anti-Anxiety Agents / Q000032:analysis* / Q000378:metabolism; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000032:analysis* / Q000378:metabolism; D001711:Biotransformation; D003653:Decarboxylation; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D007700:Kinetics; D008297:Male; D010215:Papio; D051381:Rats
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D001569:Benzodiazepines; C029617:ethyl loflazepate