液质联用法测定吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱在大鼠脑脊液和脑组织中的分布

doi:10.5246/jcps.2022.01.002

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (1): 13-22.DOI: 10.5246/jcps.2022.01.002

液质联用法测定吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱在大鼠脑脊液和脑组织中的分布

杨雁芳, 张伊楠, 张友波, 杨秀伟^*()

北京大学医学部药学院天然药物及仿生药物国家重点实验室; 天然药物学系, 北京 100191

收稿日期:2021-09-15 修回日期:2021-10-25 接受日期:2021-11-08 出版日期:2022-01-12 发布日期:2022-01-13
通讯作者: 杨秀伟
作者简介:
+ Tel.: +86-10-82801569, E-mail: xwyang@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81773865) and the National Key R&D Program of China (Grant No. 2018YFC1704500, 2018YFC1704506).

Simultaneous quantification of evodiamine, rutaecarpine, and dehydroevodiamine in rat cerebrospinal fluid and cerebral nuclei after oral administration by UPLC-MS/MS

Yanfang Yang, Yinan Zhang, Youbo Zhang, Xiuwei Yang^*()

State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2021-09-15 Revised:2021-10-25 Accepted:2021-11-08 Online:2022-01-12 Published:2022-01-13
Contact: Xiuwei Yang

摘要/Abstract

摘要：

吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱是吴茱萸中主要的生物碱类成分。为研究吴茱萸主要生物碱成分在大鼠脑脊液中的代谢和在脑组织中的分布, 吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱以1:1:1的质量比混合, 以15 mg/kg的剂量灌胃给予大鼠。本文建立了同时测定大鼠脑脊液和脑组织中三个生物碱成分的液质联用方法, 测定结果显示, 三个生物碱成分能快速吸收进入脑脊液并分布到脑组织, 并能快速消除。三个成分在脑组织中的分布特点不同, 吴茱萸碱在小脑和脑干分布最多, 而吴茱萸次碱和去氢吴茱萸碱分别在脑干、小脑和海马分布最多。本研究结果揭示了吴茱萸碱、吴茱萸次碱和去氢吴茱萸碱在脑内分布的差异, 为进一步研究中药吴茱萸果实治疗脑病的药效物质基础提供了依据。

关键词: 吴茱萸碱, 吴茱萸次碱, 去氢吴茱萸碱, 脑脊液, 脑组织, 液质联用

Abstract:

Evodiamine, rutaecarpine, and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa, a well-known traditional Chinese medicine with central nervous system activities. To study their cerebrospinal fluid pharmacokinetics and cerebral nuclei distribution, the alkaloids were mixed at the weight ratio of 1:1:1 and orally administered via gavage to the rats at each dose of 15 mg/kg. A quick and reliable ultra-performance liquid chromatographic-tandem mass spectrometry method was developed and applied for the simultaneous analysis of the alkaloids in rat cerebrospinal fluid and cerebral nuclei collected at different time points. Non-compartmental pharmacokinetic profiles were calculated, and the distribution in cerebral nuclei was compared. All the tested compounds were absorbed into rat cerebrospinal fluid and distributed to the brain nuclei quickly. Their distribution in different nuclei varied, as evodiamine mainly in cerebellum and brainstem, rutaecarpine with its maximum in the brainstem, and dehydroevodiamine mostly in the cerebellum and hippocampus. They were eliminated from the brain rapidly without long-time accumulation. In summary, this study revealed the targeting discrepancy of evodiamine, rutaecarpine, and dehydroevodiamine in the brain, and highlighted the possibility for drug candidates in the encephalopathy treatment of the fruits of E. rutaecarpa.

Key words: Evodiamine, Rutaecarpine, Dehydroevodiamine, Cerebrospinal fluid, Cerebral nuclei, UPLC-MS/MS

Supporting:

杨雁芳, 张伊楠, 张友波, 杨秀伟. 液质联用法测定吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱在大鼠脑脊液和脑组织中的分布[J]. 中国药学(英文版), 2022, 31(1): 13-22.

Yanfang Yang, Yinan Zhang, Youbo Zhang, Xiuwei Yang. Simultaneous quantification of evodiamine, rutaecarpine, and dehydroevodiamine in rat cerebrospinal fluid and cerebral nuclei after oral administration by UPLC-MS/MS[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(1): 13-22.

图/表 8

Figure 1. Chemical structures of evodiamine, rutaecarpine, dehydroevodiamine, and IS.

Table 1. Optimized MRM parameters of evodiamine, rutaecarpine, and dehydroevodiamine in mass detection.

Figure 2. MRM results of the analytes and IS in (A) cerebrospinal fluid samples (I. blank cerebrospinal fluid; II. blank cerebrospinal fluid spiked with analytes and IS; III. cerebrospinal fluid sample) and (B) nuclei samples (I. blank brain, II. blank brain spiked with analytes and IS; III. cerebellum sample; IV. cortex sample; V. brainstem sample; VI. thalamus sample; VII. hippocampus sample; VIII. striatum sample).

Table 2. The regression data, LLOQs, and LLODs of evodiamine, rutaecarpine, and dehydroevodiamine in cerebrospinal fluid and brain homogenate.

Table 3. The precision, accuracy, recovery, matrix effect, and stability of evodiamine, rutaecarpine, and dehydroevodiamine in cerebrospinal fluid and brain homogenate.

Figure 3. Concentration-time profiles of (A) three alkaloids in cerebrospinal fluid and (B) evodiamine, (C) rutaecarpine in cerebral nuclei, (D) dehydroevodiamine in cerebral nuclei after oral administration at a dose of 15 mg/kg to rats (mean ± standard deviation, n = 6).

Table 4. Pharmacokinetic parameters of evodiamine, rutaecarpine, and dehydroevodiamine in rat cerebrospinal fluid after oral administration of their mixture at each dose of 15 mg/kg (mean ± SD, n = 6).

Table 5. AUC0→∞ of evodiamine, rutaecarpine, and dehydroevodiamine in rat cerebral nuclei after oral administration of their mixture at each dose of 15 mg/kg (ng?min/mL, mean ± SD, n = 6).

参考文献 19

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液质联用法测定吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱在大鼠脑脊液和脑组织中的分布

Simultaneous quantification of evodiamine, rutaecarpine, and dehydroevodiamine in rat cerebrospinal fluid and cerebral nuclei after oral administration by UPLC-MS/MS

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