罗红霉素在苯巴比妥诱导的大鼠肝微粒体中的代谢

目的:研究罗红霉素在大鼠肝微粒体中的代谢,并考察罗红霉素及其代谢物对细胞色素P-450的影响.方法:采用超离心法制备了苯巴比妥诱导的大鼠肝微粒体酶.罗红霉素的体外代谢采用微粒体孵化方法,代谢物经LC-MS方法分离和分析,并通过进一步与合成对照品比较其质谱和色谱行为确定其结构.结果:在微粒体孵化液中发现了N-去甲基,N-双去甲基及O-去烷基三种代谢物.罗红霉素及其代谢物与CYP450 Fe~(2 )形成复合物的能力较弱.结论:罗红霉素在苯巴比妥诱导的大鼠肝微粒体中主要经历N-去甲基化和肟醚侧链O-去烷基化途径,两种转化途径均为NADPH依赖性.罗红霉素及其代谢物对CYP450的抑制作用较弱,

Metabolism of roxithromycin in phenobarbital-treated rat liver microsomes

AIM: To investigate the metabolism of roxithromycin (RXM) in rat liver microsomes and the possible effects of RXM and its metabolites on cytochrome P-450 (CYP450). METHODS: Liver microsomes of Wistar rats, induced by phenobarbital, were prepared using ultracentrituge method. RXM in vitro metabolism was studied with the microsome incubation. The metabolites were separated and assayed by liquid chromatography-tandem mass spectrometry (LC-MS"), and were further identified by comparison of their mass spectra and LC behavior to synthesized references. RESULTS: N-Mono- and A'-di-demethyl metabolites as well as O-dealkylated metabolite ( erythromycin oxime ) were detected in microsomal incubates. RXM and its metabolites expressed weak potency to form inactive complexes with CYP450. CONCLUSION: N-Deme-thylation and oxime ether side chain O-dealkylation are main biotransformation pathways of RXM in phenobarbital-treated rat liver microsomes. Both mutes were found to be NADPH-dependant. RXM and its metabolites showed weak inhibitory effects on CYP450.