左旋一叶萩碱的代谢转化

THE METABOLIC TRANSFORMATION OF (-)-SECURININE

目的 研究一叶碱 [securinine ,( - )SE]在大鼠体内外的代谢转化。方法 采用大鼠肝微粒体体外温孵法对 ( - )SE的代谢转化进行了研究 ,优化了代谢体系 ,建立了反相HPLC法同时分离检测 ( - )SE及其体外代谢产物的分析方法。用液液萃取 ,制备TLC及半制备HPLC分离纯化了 4个代谢产物并进行了光谱鉴定。在此基础上 ,建立了生物体液中 ( - )SE及其代谢物的反相HPLC分析方法 ,并用该法检测了ip给药后大鼠的胆汁、尿样及其经 β 葡糖醛酸苷酶水解后的样品。结果 代谢物分别鉴定为 6 位羟基 ,6 位羰基及 5 位α及 β羟基取代的 ( - )SE ,还证实了体内 6 位羟基代谢物进一步形成了二相结合型产物。结论 基本阐明 ( - )

AIM To study the in vitro and in vivo metabolism of (-) securinine. METHODS The metabolic transformation of (-) securinine was studied by using phenobarbital induced rat liver microsomal incubate containing the NADPH generating system in vitro and the constitution of the system was optimized. A reversed phase HPLC method was established to analyze the parent drug and its metabolites. The major metabolites were isolated and purified by liquid liquid extraction, preparative TLC and HPLC, and their structures were elucidated as 6 hydroxyl securinine, 6 carbonyl securinine, 5β hydroxyl securinine and 5α hydroxyl securinine by 1HNMR , 13 CNMR and MS spectral analysis. An HPLC method was developed to analyze securinine and its metabolites in biofluids (bile, urine) of rat. The bile, urine and their enzymatic hydrolyzed samples of the rat ip administrated with (-) securinine were determined by using this method. RESULTS Four main metabolites of (-) securinine in rat hepatic microsome incubation were obtained and their structures were elucidated. Metabolites from in vitro study were confirmed in biofluids (bile, urine) which were collected from rats given securinine ip. It was suggested that 6 hydroxyl securinine was excreted in conjugated form as well by analyzing enzymatic hydrolyzed bile. CONCLUSION The main metabolic pathway of (-) securinine in vitro and in vivo is basically elucidated.