[^(14)C]CHMFL-FLT3-122在大鼠体内的药代动力学研究  

Pharmacokinetic characteristics of [^(14)C]CHMFL-FLT3-122 in rats

作　　者：李冬阳 汪潇 鲁晓蓉 杨劲[1] 孙宏张 LI Dong-yang;WANG Xiao;LU Xiao-rong;YANG Jin;SUN Hong-zhang(China Pharmaceutical University, Nanjing 210009, China;Hefei Blooming Drug Safety Evaluation, Co. LTD., Hefei 230031, China;Hefei Cosource Pharmaceuticals Inc., Hefei 230031, China)

机构地区：[1]中国药科大学,江苏南京210009 [2]合肥合源药业有限公司,安徽合肥230031 [3]合肥诺明药物安全研究有限公司,安徽合肥230031

出　　处：《药学学报》2019年第4期714-719,共6页Acta Pharmaceutica Sinica

摘　　要：为研究CHMFL-FLT3-122在大鼠体内吸收、分布、代谢和排泄过程,采用SD大鼠口服给予50 mg·kg^(-1)[^(14)C]CHMFL-FLT3-122后收集生物样本,以放射性检测方法测定药物含量并鉴定代谢产物,本实验通过南京美新诺医药科技有限公司的实验动物伦理委员会批准。雌雄大鼠单次口服绝对生物利用度分别为50.92%和45.83%,药物吸收后主要分布于胃肠道、肝、肺中,于给药后48 h消除完全。经粪便和尿液回收药量分别占给药量的92.34%和3.99%。研究共鉴定10个Ⅰ相代谢产物和4个Ⅱ相代谢产物,主要代谢途径为N-去烃基、氧化和酰胺水解,并与硫酸和葡萄糖醛酸形成结合代谢产物。血浆中以原形为主,主要代谢产物为M553 (硫酸结合产物)和M457 (N-去烃基产物)。CHMFL-FLT3-122口服生物利用度良好,体内代谢广泛,组织分布无明显蓄积。The study was conducted to characterize the pharmacokinetics, distribution, metabolism and excretion of CHMFL-FLT3-122 after a single oral dose of 50 mg·kg-1[14C] labeled CHMFL-FLT3-122 in rats. Isotope tracing techniques were used to analyze drug concentration and identify the distribution of drugs in tissues and metabolites in biological samples. The experiments were approved by the Animal Ethics Committee of XenoBiotic Laboratories-China, Inc. The absolute bioavailability in male and female rats were 45.83% and 50.92% respectively. The parent drug and its metabolites were extensively distributed in the stomach, intestine, liver and lung, and were eliminated completely in 48 h. The majority of radioactivity was excreted through the feces at 92.34% of the dose with a small fraction through urine at 3.99% of the dose. The parent drug was the most significant circulating component, representing 49.23% and 70.65% over the 0-48 h collection time interval in the plasma of male and female. Two major metabolites, M553 (sulfate conjugate) and M457 (N-dealkyl product), were identified in plasma. Metabolites of CHMFL-FLT3-122, including ten phase I and four phase Ⅱ metabolites, were identified. The metabolic pathways of CHMFL-FLT3-122 were proposed as N-dealkylation, oxidation, amide hydrolysis, sulfate conjugation, and glucuronic conjugation.

关 键 词：CHMFL-FLT3-122 急性髓性白血病 体内代谢 ADME 放射性标记 

分 类 号：R917[医药卫生—药物分析学]