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用UHPLC-MS/MS法研究雪胆素甲在大鼠体内的代谢产物及代谢途径

Study on metabolites and metabolic pathway of curcurbitacin ⅡA in rats based on UHPLC-MS/MS
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摘要 目的建立一种快速鉴定大鼠体内雪胆素甲代谢产物的UPLC-MS/MS法,并提出可能的代谢途径。方法大鼠单次灌胃0.5%羧甲基纤维素钠配制的雪胆素甲混悬液(100 mg·kg^-1),收集大鼠给药前后的血浆和尿液。血浆经蛋白沉淀、尿液经稀释高速离心后分别进样分析。用Waters Xbridge C18色谱柱(100 mm×3 mm,3.5μm),10 mmol·L^-1乙酸铵和乙腈为流动相进行梯度洗脱,在正离子模式下对样品进行质谱分析。结果经研究分析,初步鉴定出22种雪胆素甲的代谢产物,其中包括15个Ⅰ相产物和7个Ⅱ相产物。并推测出雪胆素甲在大鼠体内的可能转化途径,包括Ⅰ相反应(水解、氧化、脱水、去甲基化)和Ⅱ相反应(葡萄糖醛酸结合、半胱氨酸结合);且雪胆素甲主要经过肾以原型及代谢产物的形式快速排泄至体外。结论本研究初步揭示了雪胆素甲在大鼠体内的代谢概况,为研究雪胆素甲代谢产物的活性及其药代动力学特性提供基础。 Objective ridentification of the metabolites of curcurbitacinⅡA in rats,and to explore its possible metabolic pathway.Methods The plasma and urine of rats were collected before and after oral administration of curcurbitacinⅡA(100 mg·kg^-1),which was suspended in 0.5%carboxymethylcellulose sodium.The plasma samples were pretreated by protein precipitation,and the urine samples were diluted,centrifuged and filtered before analysis.All samples were separated by Waters Xbridge C18 column(100 mm×3 mm,3.5μm)with a mobile phase of 10 mmol·L^-1 ammonium acetate and acetonitrile.The gradient elution was injected into the mass spectrometry in the positive ion mode.Results A total of 22 metabolites were identified in plasma and urine samples,including 15 phaseⅠmetabolites and 7 PhaseⅡmetabolites.CurcurbitacinⅡA undergone extensive biotransformation including phase I reactions(oxidation,hydroxylation,demethylation,dehydration)and phaseⅡreactions(glucuronidation,cysteine binding).The possible metabolic pathways of curcurbitacinⅡA were proposed.Moreover,CurcurbitacinⅡA was rapidly excreted in vivo primarily through the kidney in the form of prototype drug and metabolites.Conclusion For the first time,our study has unsealed the in vivo metabolic profiles of curcurbitacinⅡA in rats,providinga basis data for studying the activity of the curcurbitacinⅡA metabolites and their pharmacokinetic properties.
作者 王丽亮 袁恒杰 WANG Li-liang;YUAN Heng-jie(Department of Pharmacy,The General Hospital of Tianjin Medical University,Tianjin 300052,China)
出处 《中国临床药理学杂志》 CAS CSCD 北大核心 2020年第3期335-340,共6页 The Chinese Journal of Clinical Pharmacology
基金 国家自然科学基金资助项目(81102447,81102446) 中国博士后科学基金会课题资助项目(2013M541190).
关键词 雪胆素甲 UHPLC-MS/MS 代谢产物 代谢途径 curcurbitacinⅡA UHPLC-MS/MS metabolites metabolic pathway
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