基于二维定量核磁共振波谱技术评估调血脂临床及临床试验药物对高脂血症金黄地鼠氧化三甲胺的调节作用  

Analysis of the modulating effect of lipid-regulating clinical and clinical trial drugs on trimethylamine-oxide in hyperlipidemic hamster based on two-dimensional NMR technique

作　　者：许悦 薛仁亮 朱浩文 靳香菊 王映红 XU Yue;XUE Ren-liang;ZHU Hao-wen;JIN Xiang-ju;WANG Ying-hong(State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《药学学报》2024年第12期3354-3360,共7页Acta Pharmaceutica Sinica

基　　金：国家科技重大专项项目(2018ZX09711001-002-004);北京自然科学基金项目(7232259)

摘　　要：研究表明,心血管疾病、肾脏疾病及癌症等多种疾病与氧化三甲胺(trimethylamine-oxide,TMAO)密切相关。临床上,TMAO的异常升高已作为先于影像学的动脉粥样硬化(atherosclerosis,AS)评价指标。本研究利用高脂血症金黄地鼠模型探讨脂代谢紊乱以及药物干预对尿液中TMAO的影响。研究采用48只叙利亚金黄地鼠高脂膳食造模2周后,连续4周进行依哲麦布、辛伐他汀、依哲麦布和辛伐他汀组联合给药及临床试验药物IMM-H007药物干预。动物实验操作均遵循中国医学科学院药物研究所实验动物管理与动物福利伦理委员会的规定[批准号:SCXK (京) 2021-0011]。取金黄地鼠的给药后第2周和第4周尿液进行2D宽带选择性异核单量子相干(band selective heteronuclear single quantum coherence,2D bs-HSQC)检测。分析结果表明,与对照组相比,给药2周和4周后,高脂饮食使得模型组金黄地鼠尿液TMAO均显著升高(P <0.05)。与模型组相比,依哲麦布、辛伐他汀、联合给药以及IMM-H007给药干预2周或4周后,尿液TMAO均显著降低(P <0.05),在给药2周后已显示出明显降低,对TMAO的检测可能先于血清生化学指标检测而更早实现药效评估。本研究对临床药物及临床试验药物对TMAO的调节作用进行了评价,为临床用药及药物研究提供了有用的信息。也为TMAO的检测提供了基于2D NMR技术的检测手段,有助于TMAO检测指标的临床应用。Studies have shown that a variety of diseases such as cardiovascular disease,renal disease and cancer are closely related to trimethylamine oxide(TMAO).Clinically,abnormal elevation of TMAO has been used as an evaluation index of atherosclerosis(AS) prior to imaging.In this study,we investigated the effects of lipid metabolism disorders as well as pharmacological interventions on urinary TMAO using a hyperlipidemic golden gopher model.The study used 48 Syrian golden hamster modeled with a high-fat diet for 2 weeks,and then ezetimibe,simvastatin,ezetimibe and simvastatin groups were administered for 4 consecutive weeks,as well as the clinical trial drug,IMM-H007,for pharmacological intervention.The animal experiment was conducted in accordance with the regulations of the Ethics Committee for Experimental Animal Management and Animal Welfare of Institute of Materia Medica,Chinese Academy of Medical Sciences(approval number:SCXK(Beijing)2021-0011).Urine from rats was analyzed for 2D band selective heteronuclear single quantum coherence(2D bs-HSQC) at week 2 and 4 after drug administration.The results indicated that,in comparison to the control group,the high-fat diet significantly elevated urinary TMAO levels in the model group of hamsters after both 2 and 4 weeks of treatment(P < 0.05).Urinary TMAO levels were significantly reduced(P < 0.05) in the model group after 2 or 4 weeks of intervention with ezetimibe,simvastatin,combination therapy,and IMM-H007,showing a marked decrease even after 2 weeks of treatment.The detection of TMAO could precede the measurement of serum biochemical indicators,facilitating earlier efficacy assessment.This study evaluated the modulatory effects of clinical drugs and clinical trial drugs on TMAO,which provides useful information for clinical drug use and drug research.It also provides a means of TMAO detection based on 2D NMR technology,which is helpful for the clinical application of TMAO detection index.

关 键 词：2D NMR 氧化三甲胺 尿液 高脂血症 调血脂药物 

分 类 号：R917[医药卫生—药物分析学]