Stereoselective in vitro metabolism of rhynchophylline and isorhynchophylline epimers of Uncaria rhynchophylla in rat liver microsomes
Stereoselective in vitro metabolism of rhynchophylline and isorhynchophylline epimers of Uncaria rhynchophylla in rat liver microsomes
复制标题
钩藤碱和异钩藤碱差向异构体在大鼠肝微粒体中的体外立体选择性代谢
DOI：
10.1080/00498254.2017.1390627
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发表时间：
2018-10
期刊：
影响因子：
1.8
通讯作者：
Wu Chunyong
中科院分区：
文献类型：
--
作者：
Wang Xin;Qiao Zhou;Liu Jia;Zheng Mei;Liu Wenyuan;Wu Chunyong
1.目的探讨钩藤碱（RIN）和异钩藤碱（IRN）差向异构体在大鼠肝微粒体（RLM）中代谢的立体选择性机制。2.孵育后，利用LC-Q-TOF/MS鉴定了RIN（M1-5）和IRN（M6-8）在A环和C环上的8种代谢产物，代谢途径包括氧化、羟基化、N-氧化和脱氢。RIN的主要代谢途径为A环羟基化，IRN的主要代谢途径为C环氧化。3.酶动力学结果表明，IRN消除的固有清除率（克林特）是RIN的1.9倍，RIN的降解半衰期（T1/2）是IRN的4.7倍，表明IRN比RIN更有利于RLM的代谢。4.化学抑制研究的数据表明，CYP 3A是参与两种差向异构体代谢消除以及M1-8形成的主要亚型。5.总之，数据显示，由于C-7位的空间构型，RIN和IRN差向异构体具有不同的肝脏代谢途径和消除速率，这些代谢途径和消除速率主要由CYP 3A介导。
1. The objective was to investigate the underlying mechanism of the stereoselectivity in the metabolism of rhynchophylline (RIN) and isorhynchophylline (IRN) epimers in rat liver microsomes (RLM). 2. After incubation, eight metabolites of RIN (M1-5) and IRN (M6-8) reacted at A- and C-ring were identified using LC-Q-TOF/MS. Metabolic pathways included oxidation, hydroxylation, N-oxidation and dehydrogenation. In addition, hydroxylation at A-ring was the major metabolic pathway for RIN whereas the oxidation at C-ring was the major one for IRN. 3. Enzyme kinetics showed that the intrinsic clearance (CLint) for IRN elimination was 1.9-fold higher than RIN and the degradation half-life (T1/2) of RIN was 4.7-fold higher than that of IRN, indicating IRN was more favorable to be metabolized than RIN in RLM. 4. Data from chemical inhibition study demonstrated CYP3A was the predominant isoform involved in the metabolic elimination of both epimers, as well as the formation of M1-8. 5. In conclusion, data revealed that due to the spatial configurations at C-7 position, RIN and IRN epimers possessed different hepatic metabolic pathways and elimination rates which were mainly mediated by CYP3A.
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DOI：
10.1002/bmc.3149
发表时间：
2014-09
期刊：
Biomedical chromatography : BMC
影响因子：
--
作者：
Wei Wang;Xin-Mei Li;Yaping Chen;M. Hattori
通讯作者：
Wei Wang;Xin-Mei Li;Yaping Chen;M. Hattori
DOI：
10.1016/j.jchromb.2016.08.013
发表时间：
2016-10
期刊：
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
影响因子：
--
作者：
Jian-wei Wang;Peng Qi;Jinjun Hou;Yao Shen;Bing-peng Yan;Qi-rui Bi;Rui-hong Feng;Xiao-jian Shi;Min Yang;Wan-ying Wu;D. Guo
通讯作者：
Jian-wei Wang;Peng Qi;Jinjun Hou;Yao Shen;Bing-peng Yan;Qi-rui Bi;Rui-hong Feng;Xiao-jian Shi;Min Yang;Wan-ying Wu;D. Guo
影响因子：
1.8
作者：
Peng, Ying;Wu, Hui;Sun, Jianguo
通讯作者：
Sun, Jianguo
影响因子：
3.9
作者：
Bjornsson, TD;Callaghan, JT;Wrighton, SA
通讯作者：
Wrighton, SA
影响因子：
13.3
作者：
Lu, Jia-Hong;Tan, Jie-Qiong;Li, Min
通讯作者：
Li, Min