五味子醇甲在大鼠肝微粒体内的代谢动力学和性别差异  

Enzyme kinetics of schizandrin metabolism and sex differences in rat liver microsomes

作　　者：许美娟[1] 王广基[2] 谢海棠[3] 黄青[2] 贾元威[2] 

机构地区：[1]江苏省中医院临床药理科,江苏南京210029 [2]中国药科大学药物代谢动力学重点实验室,江苏南京210009 [3]皖南医学院弋矶山医院,安徽芜湖241001

出　　处：《药学学报》2007年第7期730-734,共5页Acta Pharmaceutica Sinica

基　　金：国家高技术研究发展计划(863计划)"临床前药物代谢动力学关键技术及平台研究"项目(2003AA2Z3471;2005AA2Z3C70)

摘　　要：体外研究五味子醇甲(schizandrin,SZ)在大鼠肝微粒体内的代谢动力学和性别差异。制备正常雌、雄大鼠肝微粒体,与SZ共同温孵,以高效液相色谱法测定SZ及其代谢产物。SZ在雄鼠肝微粒体内代谢反应的最大速率Vmax、米氏常数Km和清除率Clint分别为(21.88±2.30)μmol·L-1.min-1·mg-1(protein),(389.00±46.26)μmol·L-1和(0.0563±0.0007)min·mg-1(protein);在雌鼠肝微粒体内代谢反应的最大速率Vmax、米氏常数Km和清除率Clint分别为(0.61±0.07)μmol·L-1·min-1.mg-1(protein),(72.64±13.61)μmol·L-1和(0.0084±0.0008)min·mg-1(protein),雌、雄鼠肝微粒体内SZ的主要代谢物不同,分别为7,8-顺二羟基五味子醇甲(M1)和7,8-顺二羟基-2-去甲基五味子醇甲(M2b)。酮康唑、奎尼丁和奥芬得林对SZ的在雌、雄大鼠肝微粒体内代谢均有不同程度的抑制作用,西咪替丁对其在雄鼠肝微粒体内的代谢也有一定的抑制作用。SZ在雌、雄大鼠肝微粒体中代谢动力学及代谢产物存在明显的性别差异,这种差异可能主要是由CYP3A和CYP2C11在大鼠肝微粒体内的性别差异引起的。To study the enzyme kinetics of schizandrin metabolism in different gender in rat liver microsomes, liver microsomes were prepared from male or female rats. Schizandrin was incubated with rat liver microsomes. Schizandrin and its metabolites were isolated and identified by HPLC-UV method. Vmax Km and Clint of schizandrin in male and female rat liver microsomes were （21.88 ＋ 2.30） and （0.61 ＋ 0.07） μmol· L^-1·min^-1· mg^-1（protein）, （389.00 ＋46.26） and （72.64＋13.61） μmol· L^-1（0.056 3 ＋0.000 7） and （0.008 4 ＋ 0.000 8） min· mg^-1 （protein）, respectively. The major metabolites of schizandrin in female and male rat liver microsomes were 7,8-dihydroxy-schizandrin （ M1 ） and 7, 8-dihydroxy-2-demethyl schizandrin （ M2b ） , respectively. Ketoconazole, quinidine, and orphenadrine had different level effects on schizandrin metabolism in both male and female rat liver microsomes, and cimetidine still had some inhibitory effect in male liver microsomes. CYP3A and CYP2Cll may be the main P450 enzymes in schizandrin metabolism and their difference in rat liver microsomes may be the main reason for the sex difference of metabolic enzyme kinetics and metabolites of schizandrin in rats.

关 键 词：五味子醇甲 代谢 性别差异 细胞色素P450 肝微粒体 

分 类 号：R917[医药卫生—药物分析学] R969.1[医药卫生—药学]