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  • 1
    Electronic Resource
    Electronic Resource
    Metabolism of halazepam by rat liver microsomes: Stereoselective formation and n-dealkylation of 3-hydroxyhalazepam (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 2 (1990), S. 1-9 
    Details
    ISSN: 0899-0042
    Keywords: halazepam ; 3-hydroxyhalazepam ; diazepam ; N-desmethyldiazepam ; oxazepam ; enantiomers ; rat liver microsomes ; stereoselectivity ; enantioselectivity ; hydroxylation ; enantioselective N-dealkylation ; kinetics of racemization ; circular dichroism spectra ; chiral stationary phase ; high-performance liquid chromatography ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Metabolism of halazepam [7-chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodi epin-2-one, HZ] was studied by incubation with liver microsomes prepared from untreated, phenobarbital (PB)-treated, and 3-methylcholanthrene (3MC)-treated male Sprague-Dawley rats. Metabolites of HZ were separated by normal-phase HPLC. Relative rates of HZ metabolism by liver microsomes prepared from untreated and treated rats were PB-treated ≫ untreated 〉 3MC-treated at low concentration of microsomal enzymes (0.25 mg protein per ml of incubation mixture) and PB-treated ≫ 3MC-treated ≈ untreated at high concentration of microsomal enzymes (2 mg protein per ml of incubation mixture). The relative amounts of major metabolites were found to be 3-hydroxy-HZ (3-OH-HZ) 〉 N-desalkylhalazepam (NDZ, also known as N-desmethyldiazepam and nordiazepam) ≫ oxazepam (OX) for all three rat liver microsomal preparations and the distribution of metabolites was independent of microsomal enzyme concentrations. Enantiomers of 3-OH-HZ were resolved by HPLC on a Chiralcel OC column (cellulose trisphenylcarbamate coated on silica gel, particle size 10 μm). 3-OH-HZ enantiomeres have racemization half-lives of ∼ 150 min in pH 4,7.5, and 10 aqueous solutions. 3-OH-HZ formed in the metabolism of HZ by liver microsomes prepared from untreated and treated rats were found to have 3R/3S enantiomer rations of 37/63 (untreated), 55/45 (PB-treated), and 36/64 (3MC-treated), respectively. N-dealkylation of 3-OH-HZ by liver microsomes from PB-treated rats was substrate enantioselective; the 3R-enantiomer was N-dealkylated faster than 3S-enantiomer. The results indicated that the stereoselective C3-hydroxylation of HZ is dependent on the cytochromes P-450 present in the rat liver microsomal preparations; pro-R in liver microsomes from PB-treated rats and pro-S in liver microsomes from untreated and 3MC-treated rats, respectively.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530020102
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  • 2
    Electronic Resource
    Electronic Resource
    Enantioselective hydrolysis of oxazepam 3-acetate by esterases in human and rat liver microsomes and rat brain s9 fraction (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 2 (1990), S. 150-155 
    Details
    ISSN: 0899-0042
    Keywords: oxazepam ; 3-O-acyloxazepam (oxazepam 3-acetate) ; diazepam ; N-desmethyldiazepam ; enantiomers ; esterases ; rat brain S9 fraction ; rat liver microsomes ; human liver microsomes ; enantioselective hydrolysis ; chiral stationary phase ; high-performance liquid chromatography ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Rates of hydrolysis of racemic and enantiomeric oxazepam 3-acetates (OXA) by esterases in human and rat liver microsomes and rat brain S9 fraction were compared. When rac-OXA was the substrate, esterases in human and rat liver microsomes were highly enantioselective toward (R)-OXA. In contrast, esterases in rat brain S9 fraction were highly enantioselective toward (S)-OXA. Hydrolysis rates of rac-OXA were highly dependent on the amount of esterases used. At 0.05 mg protein equivalent of esterases and 150 nmol of rac-OXA per ml of incubation mixture, the (R)-OXA was hydrolyzed 3.6-fold and 18.5-fold faster than (S)-OXA by rat and human liver microsomes, respectively. The specific activities (nmol of OXA hydrolyzed/mg microsomal protein/min) of liver microsomes in the hydrolysis of enantiomerically pure (R)-OXA were approximately 120 (rat) and 1,980 (human), and in the hydrolysis of enantiomerically pure (S)-OXA were 4 (rat) and 7 (human), respectively. In the incubation of rac-OXA with rat brain S9 fraction, (S)-OXA was hydrolyzed ∼6-fold faster than (R)-OXA. Results also indicated an enantiomeric interaction in the hydrolysis of rac-OXA by esterases in rat and human liver microsomes; the presence of (R)-OXA stimulated the hydrolysis of (S)-OXA, whereas the presence of (S)-OXA inhibited the hydrolysis of (R)-OXA. In rat brain S9 fraction, the presence of (R)-OXA inhibited the hydrolysis of (S)-OXA, whereas the presence of (S)-OXA appeared to have stimulated the hydrolysis of (R)-OXA.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530020305
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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