Enantiomer resolution of camazepam and its derivatives and enantioselective metabolism of camazepam by human liver microsomes.
Camazepam [3-(N,N-dimethyl)carbamoyloxy-7-chloro-1-methyl-1,3-dihydro- 5-phenyl-2H-1,4-benzodiazepin-2-one, CMZ] possesses anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. CMZ is clinically used as a racemate. Enantiomer resolution of CMZ and 11 of its derivatives was studied by high-performance liquid chromatography (HPLC) using 5 different chiral stationary phase (CSP) columns. Enantiomers of 10 compounds were resolved by at least one of the 5 CSP's tested. Enantiomers of two other compounds, which have either one or two hydroxymethyl groups at the carbamoyl nitrogen, were either not resolved or resolved with very low efficiency. However, enantiomers of the hydroxymethyl derivatives were resolved via base-catalyzed dehydroxymethylation. In vitro metabolism of racemic CMZ by human liver microsomes was found to be enantioselective. Major metabolites were isolated by normal-phase and reversed-phase HPLC and further characterized by ultraviolet absorption and circular dichroism spectral analyses, and by chiral stationary phase HPLC analysis. Following an in vitro incubation of rac-CMZ, the unmetabolized CMZ was found to be enriched in (S)-CMZ, indicating that the R-enantiomer was enantioselectively metabolized. Metabolites were formed primarily by hydroxylation and demethylation of the methyl groups at the C3 side chain. All metabolites were found to be optically active, enriched in either the S-enantiomer or the R-enantiomer.
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Department of Pharmacology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
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D000328:Adult; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013693:Temazepam / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism*
D013693:Temazepam