去氢骆驼蓬碱在大鼠体内代谢产物与代谢途径的UPLC-Q-TOF-MS分析  

Analysis on Metabolites and Metabolic Pathways of Harmine in Rats by UPLC-Q-TOF-MS

作　　者：卡地尔亚·库尔班 王长虹[2] 徐楠 徐勤伟 滕亮[3] 高惠静[3] CARTIERA Kurban;WANG Changhong;XU Nan;XU Qinwei;TENG Liang;GAO Huijing(School of Pharmacy,Xinjiang Medical University,Urumqi 83001l,China;Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia,The First Affiliated Hospital of Xinjiang Medical University,Urumqi 830054,China)

机构地区：[1]新疆医科大学药学院,乌鲁木齐830011 [2]上海中医药大学中药研究所,上海201203 [3]新疆医科大学第一附属医院,省部共建中亚高发病成因与防治国家重点实验室,乌鲁木齐830054

出　　处：《中国实验方剂学杂志》2024年第11期202-209,共8页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：省部共建中亚高发病成因与防治国家重点实验室开放课题(SKL-HIDCA-2022-BC3,SKL-HIDCA-2023-YX1);新疆维吾尔自治区重点研发项目(2022B03013-4);中华国际医学交流会基金会——中华医学会临床药学分会2023年度临床药学科研基金(Z-2021-46-2101-2023);兵团科技攻关计划项目(2023AB009-04);新疆维吾尔自治区自然科学基金项目(2023D01A120)。

摘　　要：目的:采用超高效液相色谱-四极杆-飞行时间质谱法(UPLC-Q-TOF-MS)鉴定去氢骆驼蓬碱在大鼠体内的代谢产物,探究去氢骆驼蓬碱单剂量灌胃给药后在大鼠体内代谢产物分布差异,并推测其代谢途径。方法:SD大鼠单剂量(40 mg·kg^(-1))灌胃给予去氢骆驼蓬碱,收集给药后血浆、胆汁、尿液和粪便样品,经处理后运用UPLC-Q-TOF-MS进行分析,采用ACQUITY UPLCTMHSS T3色谱柱(2.1 mm×100 mm,1.8μm),乙腈(A)-0.1%甲酸水溶液(B)为流动相进行梯度洗脱(0~2 min,5%A;2~9 min,5%~35%A;9~9.5 min,35%~100%A;9.5~12 min,100%A;12~12.5 min,100%~5%A;12.5~14 min,5%A),质谱采用电喷雾离子化源(ESI),正离子检测模式,扫描范围m/z 50~1 200。根据得到的化合物相对保留时间、准分子离子峰及特征碎片离子等信息,与文献数据进行比较,鉴定去氢骆驼蓬碱体内代谢产物,并推测其代谢途径。结果:在大鼠血浆、胆汁、尿液和粪便中共鉴定出去氢骆驼蓬碱及其相关代谢产物42个,其中血浆中27个,胆汁中17个,尿液中26个,粪便中13个。涉及的代谢途径包括单羟基化、双羟基化、去甲基化、葡萄糖醛酸化及硫酸化等。结论:去氢骆驼蓬碱可在大鼠体内发生Ⅰ相和Ⅱ相代谢反应,原型药物在体内代谢较快,代谢产物主要经肾脏排泄,可为去氢骆驼蓬碱的药效学和物质基础研究提供参考依据。Objective: Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was used to identify the metabolites of harmine in rats, in order to explore the differences in distribution of metabolites in rats after single dose(40 mg·kg^(-1)) intragastric administration of harmine, as well to speculate the metabolic pathways. Method: SD rats were given a single dose of harmine by intragastric administration. Plasma, bile, urine and feces samples were collected after administration, and the samples were processed for determination by UPLC-Q-TOF-MS. The separation was performed on an ACQUITY UPLC^(TM) HSS T3 columu(2.1 mm×100 mm, 1.8 μm) with acetonitrile(A)-0.1% formic acid aqueous solution(B) as mobile phase for gradient elution(0-2 min, 5%A;2-9 min, 5%-35%A;9-9.5 min, 35%-100%A;9.5-12 min, 100%A;12-12.5 min, 100%-5%A;12.5-14 min, 5%A), the mass spectra were obtained in positive ion mode with electrospray ionization(ESI), the scanning range was m/z 50-1 200. The metabolites of harmine were identified based on the information of the obtained compounds and the literature data, and the metabolic pathways were hypothesized. Result: A total of 42 compounds(harmine and its metabolites) were identified in rats, including 27 in plasma, 17 in bile, 26 in urine and 13 in feces. The metabolic pathways involved in these 42 metabolites included monohydroxylation, dihydroxylation, demethylation, glucuronidation and sulfation.Conclusion: Harmine can undergo phase Ⅰ and phase Ⅱ metabolic reactions in rats, and the prototype drug is metabolized rapidly in vivo, and the metabolites are mainly excreted by the kidneys, which can provide a reference basis for the pharmacodynamics and material basis of harmine.

关 键 词：去氢骆驼蓬碱 超高效液相色谱-四极杆-飞行时间质谱法(UPLC-Q-TOF-MS) 代谢产物 代谢途径 血浆 胆汁 尿液 

分 类 号：R22[医药卫生—中医基础理论] R969.1[医药卫生—中医学] R28[理学—分析化学] O657[理学—化学]