Metabolism of halazepam by rat liver microsomes: stereoselective formation and N-dealkylation of 3-hydroxyhalazepam.
Metabolism of halazepam by rat liver microsomes: stereoselective formation and N-dealkylation of 3-hydroxyhalazepam.
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DOI：
10.1002/chir.530020102
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发表时间：
1990
期刊：
影响因子：
2
通讯作者：
X. Lu;S. K. Yang
中科院分区：
文献类型：
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作者：
X. Lu;S. K. Yang
用未处理、苯巴比妥（PB）处理和3-甲基胆蒽（3MC）处理的雄性Sprague-Dawley大鼠肝微粒体孵育研究了halazepam[7-氯-1,3-二氢-5-苯基-1-（2,2,2-三氟乙基）- 2h -1,4-苯氮平-2 -one， HZ]的代谢。采用正相高效液相色谱法分离其代谢物。在低浓度的微粒体酶（0.25 mg蛋白/ ml孵育液）条件下，pb处理大鼠肝微粒体的相对HZ代谢率远高于未处理大鼠，也远高于3mc处理大鼠；在高浓度的微粒体酶（2 mg蛋白/ ml孵育液）条件下，pb处理大鼠的相对HZ代谢率远高于3mc处理大鼠。三种大鼠肝微粒体制剂中主要代谢物的相对量均大于n -脱盐基氮西泮（NDZ，也称为n -去甲基地西泮和去甲地西泮），且代谢物的分布与微粒体酶浓度无关。3-OH-HZ的对映体在Chiralcel OC柱（三苯基氨基甲酸纤维素包被硅胶，粒径为10微米）上进行高效液相色谱分析。3-OH-HZ对映体在pH值为4、7.5和10的水溶液中的外消旋半衰期约为150分钟。未处理和处理大鼠肝微粒体代谢HZ形成的3-OH-HZ的3R/3S对映体比例分别为37/63（未处理），55/45 （pb处理）和36/64 （3mc处理）。pb处理大鼠肝微粒体对3-OH-HZ的n -脱烷基具有底物对映选择性；3r对映体比3s对映体的n -脱烷基速度快。（摘要删节250字）
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)