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Metabolism of halazepam by rat liver microsomes: stereoselective formation and N-dealkylation of 3-hydroxyhalazepam.
Chirality. 1990; 2(1):1-9.C

Abstract

Metabolism of halazepam [7-chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4-benzod iazepin- 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 much greater than untreated greater than 3MC-treated at low concentration of microsomal enzymes (0.25 mg protein per ml of incubation mixture) and PB-treated much greater than 3MC-treated approximately 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) greater than N-desalkylhalazepam (NDZ, also known as N-desmethyldiazepam and nordiazepam) much greater than 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 microns). 3-OH-HZ enantiomeres have racemization half-lives of approximately 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 ratios 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Lu XL
Department of Pharmacology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799.
Yang SK
No affiliation info available

MeSH

AnimalsAnti-Anxiety AgentsBenzodiazepinesBenzodiazepinonesChromatography, High Pressure LiquidCytochrome P-450 Enzyme SystemDealkylationEnzyme InductionHalf-LifeHumansKineticsMaleMicrosomes, LiverRatsRats, Inbred StrainsSpectrophotometry, UltravioletStereoisomerism

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

2400636

Citation

Lu, X L., and S K. Yang. "Metabolism of Halazepam By Rat Liver Microsomes: Stereoselective Formation and N-dealkylation of 3-hydroxyhalazepam." Chirality, vol. 2, no. 1, 1990, pp. 1-9.
Lu XL, Yang SK. Metabolism of halazepam by rat liver microsomes: stereoselective formation and N-dealkylation of 3-hydroxyhalazepam. Chirality. 1990;2(1):1-9.
Lu, X. L., & Yang, S. K. (1990). Metabolism of halazepam by rat liver microsomes: stereoselective formation and N-dealkylation of 3-hydroxyhalazepam. Chirality, 2(1), 1-9.
Lu XL, Yang SK. Metabolism of Halazepam By Rat Liver Microsomes: Stereoselective Formation and N-dealkylation of 3-hydroxyhalazepam. Chirality. 1990;2(1):1-9. PubMed PMID: 2400636.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolism of halazepam by rat liver microsomes: stereoselective formation and N-dealkylation of 3-hydroxyhalazepam. AU - Lu,X L, AU - Yang,S K, PY - 1990/1/1/pubmed PY - 1990/1/1/medline PY - 1990/1/1/entrez SP - 1 EP - 9 JF - Chirality JO - Chirality VL - 2 IS - 1 N2 - Metabolism of halazepam [7-chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4-benzod iazepin- 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 much greater than untreated greater than 3MC-treated at low concentration of microsomal enzymes (0.25 mg protein per ml of incubation mixture) and PB-treated much greater than 3MC-treated approximately 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) greater than N-desalkylhalazepam (NDZ, also known as N-desmethyldiazepam and nordiazepam) much greater than 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 microns). 3-OH-HZ enantiomeres have racemization half-lives of approximately 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 ratios 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.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0899-0042 UR - https://www.unboundmedicine.com/medline/citation/2400636/Metabolism_of_halazepam_by_rat_liver_microsomes:_stereoselective_formation_and_N_dealkylation_of_3_hydroxyhalazepam_ DB - PRIME DP - Unbound Medicine ER -