基于UPLC-Q-Exactive Orbitrap MS分析天维菌素在大鼠和犬肝微粒体的代谢产物

doi:10.3864/j.issn.0578-1752.2026.09.013

中国农业科学 ›› 2026, Vol. 59 ›› Issue (9): 2016-2028.doi: 10.3864/j.issn.0578-1752.2026.09.013

基于UPLC-Q-Exactive Orbitrap MS分析天维菌素在大鼠和犬肝微粒体的代谢产物

刘晓华¹^,²(), 梁健平¹^,²(), 刘燕³, 吴诚煜², 张益诚², 黄显会¹^,²(), 李向梅¹^,²()

¹ 华南农业大学食品学院/广东省食品质量安全重点实验室，广州 510642
² 华南农业大学兽医学院/广东省兽药研制与安全评价重点实验室，广州 510642
³ 广东省农产品质量安全中心（广东省绿色食品发展中心），广州 510523

收稿日期:2025-11-17 接受日期:2026-03-18 出版日期:2026-05-01 发布日期:2026-05-06
通信作者:
李向梅，E-mail：lixiangmei12@163.com。
黄显会，E-mail：xhhuang@scau.edu.cn
联系方式: 刘晓华，E-mail：liuxiaohua9909@163.com。梁健平，E-mail：1304016829@qq.com。刘晓华与梁健平是同等贡献作者。
基金资助:
“十四五”国家重点研发计划(2022YFD1802105)

In vitro Metabolites of Tenvermectin in Rat and Dog Liver Microsomes Analyzed by UPLC-Q-Exactive Orbitrap MS

LIU XiaoHua¹^,²(), LIANG JianPing¹^,²(), LIU Yan³, WU ChengYu², ZHANG YiCheng², HUANG XianHui¹^,²(), LI XiangMei¹^,²()

¹ Guangdong Provincial Key Laboratory of Food Quality and Safety/College of Food Science, South China Agricultural University, Guangzhou 510642
² Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation/College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642
³ Guangdong Centre for Agricultural Products Quality and Safety (Guangdong Green Food Development Center), Guangzhou 510523

Received:2025-11-17 Accepted:2026-03-18 Published:2026-05-01 Online:2026-05-06

摘要/Abstract

摘要：

【目的】天维菌素（tenvermectin, TVM）是通过对阿维菌素产生菌和米尔贝霉素产生菌的基因修饰，构建出了新的工程菌的次级代谢产物，属于新型十六元环大环内酯类药物，采用高分辨质谱技术分析鉴定新兽药TVM在肝微粒体模型中的体外代谢产物，直接反映药物的体外代谢特征，同时为体内代谢研究提供了理论基础和重要线索。【方法】通过差速离心法制备大鼠和犬肝微粒体，并通过分别与大鼠肝微粒体特异性底物7-乙氧基香豆素、犬肝微粒体特异性底物香豆素孵育的方式确定了两者均具有体外代谢活性，建立了TVM的体外肝微粒体代谢模型。在体外的条件下，通过大鼠、犬肝微粒体与TVM进行孵育，对孵育体系中的代谢物提取净化。采用超高效液相色谱-四极杆-静电场轨道阱高分辨质谱（UPLC-Q-Exactive Orbitrap MS）检测TVM代谢物，通过代谢物软件预测、仪器验证的方式确定代谢物是否存在，同时结合原形天维菌素的元素组成和结构，对每个代谢物及其碎片离子进行快速准确的鉴定。【结果】在大鼠肝微粒体孵育体系中检测到九种TVM代谢产物，包括去甲基化产物（M2、M5、M8）、氧化产物（M1、M3、M4、M9）、酮化产物（M6）以及去单糖化产物（M7）。相比之下，在犬肝微粒体孵育体系中则检测到10种TVM代谢产物，涵盖去甲基产物（M2、M5、M8）、氧化产物（M9、M10、M11、M13）、酮化产物（M6）、去单糖化产物（M7），部分去甲基化产物会继续酮化形成去甲基化后酮化产物（M12）。TVM在两个种属的肝微粒体中代谢物种类以及含量均存在差异。【结论】利用UPLC-Q-Exactive Orbitrap MS对TVM的代谢产物和代谢途径进行研究，TVM在大鼠和犬肝微粒体的体外代谢途径包括去甲基化、氧化、酮化、去单糖化和去甲基化后酮化等，其中以去甲基化和氧化为主，阐明了天维菌素的体外代谢方式，完善其代谢途径。研究结果为进一步研究TVM在动物体内的代谢产物、药代动力学及药效学提供了重要的理论基础和参考依据。

关键词: 天维菌素, 代谢产物鉴定, UPLC-Q-Exactive Orbitrap MS, 肝微粒体, 代谢途径

Abstract:

【Objective】Tenvermectin (TVM) is a novel 16-membered macrolide antibiotic synthesized from genetically engineered bacteria that produce avermectin and milbemycin. The in vitro metabolites of the new veterinary drug Tenvermectin (TVM) in the liver microsomal model were analyzed and identified by high-resolution mass spectrometry. It directly reflects the in vitro metabolic characteristics of the drug, and at the same time provides a theoretical basis and important clues for in vivo metabolic studies.【Method】In this study, rat and dog liver microsomes were first prepared by differential centrifugation. The in vitro metabolic activities of both were determined by incubating them with specific substrates for rat liver microsomes (7-ethoxy coumarin) and dog liver microsomes (coumarin), respectively. An in vitro liver microsome metabolic model of TVM was established. Under in vitro conditions, the metabolites in the incubation system were extracted and purified by incubating rat and dog liver microsomes with TVM. The metabolites of TVM were detected by UPLC-Q-Exactive Orbitrap MS. The existence of the metabolites was determined through software prediction and instrument verification of the metabolites. At the same time, combined with the elemental composition and structure of the original tetraviridin, each metabolite and its fragment ions were rapidly and accurately identified.【Result】The findings indicated that nine TVM metabolites were identified in rat liver microsomes, comprising demethylated products (M2, M5, M8), oxidized products (M1, M3, M4, M9), ketone products (M6), and demonosaccharified products (M7). In contrast, ten TVM metabolites were detected in dog liver microsomes, including demethylated products (M2, M5, M8), oxidized products (M9, M10, M11, M13), ketone products (M6), demonosaccharified products (M7), and demethylated ketone products (M12). The metabolite types and contents in the liver microsomes of the two species were different.【Conclusion】UPLC-Q-Exactive Orbitrap MS was used to study the metabolites and metabolic pathways of TVM. The metabolic pathways of TVM in rat and dog liver microsome in vitro included demethylation, oxidation, ketonization, demonoglycation and ketonization after demethylation, among which demethylation and oxidation were the main ones. This research clarified the in vitro metabolic mode of tenvermectin and refined its metabolic pathway. The research results provide an important theoretical basis and reference for further studying the metabolic products, pharmacokinetics and pharmacodynamics of TVM in animals.

Key words: tenvermectin, metabolites identification, UPLC-Q-exactive orbitrap MS, liver microsomes, metabolic pathway

刘晓华, 梁健平, 刘燕, 吴诚煜, 张益诚, 黄显会, 李向梅. 基于UPLC-Q-Exactive Orbitrap MS分析天维菌素在大鼠和犬肝微粒体的代谢产物[J]. 中国农业科学, 2026, 59(9): 2016-2028.

LIU XiaoHua, LIANG JianPing, LIU Yan, WU ChengYu, ZHANG YiCheng, HUANG XianHui, LI XiangMei. In vitro Metabolites of Tenvermectin in Rat and Dog Liver Microsomes Analyzed by UPLC-Q-Exactive Orbitrap MS[J]. Scientia Agricultura Sinica, 2026, 59(9): 2016-2028.

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代谢产物编号 Metabolite ID	代谢方式 Pathway	分子式 Formula	预测分子量 Neutral mass (Da)	m/z [M+Na]⁺	质量误差 Mass accuracy (ppm)	保留时间 R.T. (min)	峰面积 Peak area	相对含量 Relative content (%)
TVM	原型Prototype	C₄₆H₇₀O₁₄	846.4760081	869.46417	-1.85	15.71	6.60E+09	-
M1	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45898	-1.93	15.46	1.08E+08	7.40
M2	去甲基化Demethylation	C₄₅H₆₈O₁₄	832.4603580	855.44836	-2.07	15.39	3.44E+08	23.57
M3	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45825	-2.76	15.35	3.35E+07	2.30
M4	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45821	-2.80	15.29	9.41E+06	0.64
M5	去甲基化Demethylation	C₄₅H₆₈O₁₄	832.4603580	855.44855	-1.84	15.27	3.12E+07	2.14
M6	酮化Ketone formation	C₄₆H₆₈O₁₅	860.4552726	883.44324	-2.04	15.23	3.08E+08	21.11
M7	去单糖化Loss of C₇H₁₂O₃	C₃₉H₅₈O₁₁	702.3973639	725.38541	-2.38	14.92	1.43E+07	0.98
M8	去甲基化Demethylation	C₄₅H₆₈O₁₄	832.4603580	855.44861	-1.77	14.84	8.82E+06	0.60
M9	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45898	-1.93	12.86	6.02E+08	41.25

代谢产物编号 Metabolite ID	代谢方式 Pathway	分子式 Formula	预测分子量 Neutral mass（Da）	m/z [M+Na]⁺	质量误差 Mass accuracy (ppm)	保留时间 R.T. (min)	峰面积 Peak area	相对含量 Relative content (%)
TVM	原型Prototype	C₄₆H₇₀O₁₄	846.4760081	869.46472	-1.22	15.69	7.15E+09	-
M2	去甲基化Demethylation	C₄₅H₆₈O₁₄	832.4603580	855.44855	-1.84	15.40	1.27E+09	60.00
M5	去甲基化Demethylation	C₄₅H₆₈O₁₄	832.4603580	855.44928	-0.99	15.26	3.68E+07	1.74
M6	酮化Ketone formation	C₄₆H₆₈O₁₅	860.4552726	883.44364	-1.59	15.23	8.58E+07	4.05
M7	去单糖化Loss of C₇H₁₂O₃	C₃₉H₅₈O₁₁	702.3976390	725.38568	-2.00	14.91	2.19E+07	1.03
M8	去甲基化Demethylation	C₄₅H₆₈O₁₄	832.4603580	855.44806	-2.42	14.84	2.99E+07	1.41
M9	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45892	-2.00	12.89	5.41E+07	2.56
M10	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45813	-2.89	15.42	2.23E+07	1.05
M11	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45911	-1.79	15.12	4.70E+08	22.20
M12	去甲基化后酮化Demethylation and ketone formation	C₄₅H₆₆O₁₅	846.4396226	869.42798	-1.62	14.94	2.30E+07	1.09
M13	氧化Oxidation	C₄₆H₇₀O₁₅	862.4709227	885.45874	-2.20	14.59	1.03E+08	4.87

基于UPLC-Q-Exactive Orbitrap MS分析天维菌素在大鼠和犬肝微粒体的代谢产物

In vitro Metabolites of Tenvermectin in Rat and Dog Liver Microsomes Analyzed by UPLC-Q-Exactive Orbitrap MS

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