Pharmacokinetics and Urine Metabolite Identification of Dehydroevodiamine in the Rat
Pharmacokinetics and Urine Metabolite Identification of Dehydroevodiamine in the Rat
复制标题
DOI：
10.1021/jf204365m
复制
发表时间：
2012-02-22
影响因子：
6.1
通讯作者：
Tsai, Tung-Hu
中科院分区：
文献类型：
--
作者：
Lin, Lie-Chwen;Li, Shang-Hua;Tsai, Tung-Hu
本研究研究了脱氢evolodiamine （DeHE）的口服生物利用度，并对其尿液代谢产物进行了表征。脱氢evolodiamine是一种从吴茱萸果实中分离出来的生物碱。采用自由运动大鼠模型和自动采血系统对德贺的药代动力学进行了评价。采用高效液相色谱法（HPLC）、质谱法（MS）、核磁共振（NMR）等方法测定DeHE及其代谢物。在自由活动大鼠中，100和500 mg/kg的平均口服生物利用度约为15.35%。单次口服（500 mg/kg）德荷后，未改变的德荷的累积粪便和尿液排泄量分别为6%和0.5%。DeHE在大鼠血浆中的蛋白结合率为65.6 +/- 6.5%。口服给药后鉴定出6种代谢物，包括5种DeHE-O-glucuronides和1种Del-LE sulfate。确定了两种葡萄糖醛酸缀合物dehe -10- o -葡萄糖醛酸（M3）和dehe -11- o -葡萄糖醛酸（M4）以及一种硫酸盐缀合物dehe -12-硫酸盐（M6）的结构。研究结果表明，德贺的口服生物利用度远高于evolodiamine，并且在尿中消除德贺需要羟基化和结合代谢。
This study investigates the oral bioavailability and characterizes urine metabolites of dehydroevodiamine (DeHE), one of the bioactive alkaloids isolated from the fruit of Evodia rutaecarpa. A freely moving rat model coupled with an automated blood sample system was used to evaluate the pharmacokinetics of DeHE. High-performance liquid chromatography (HPLC), mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectrometry were applied to determine DeHE and its metabolites. The averaged oral bioavailability of DeHE (100 and 500 mg/kg) in the freely moving rats was approximately 15.35%. Cumulative fecal and urinary excretions of unchanged DeHE were 6 and 0.5%, respectively, after a single oral dose (500 mg/kg) of DeHE. The protein binding of DeHE in rat plasma was 65.6 +/- 6.5%. Six metabolites, including five DeHE-O-glucuronides and one Del-LE sulfate, were identified after oral administration. The structures of two glucuronide conjugates, DeHE-10-O-glucuronide (M3) and DeHE-11-O-glucuronide (M4), and one sulfate conjugate, DeHE-12-sulfate (M6), were assigned. The findings indicate that the oral bioavailability of DeHE was much higher than that of evodiamine, and hydroxylation and conjugative metabolism were essential for the urinary elimination of DeHE.