盐酸丁咯地尔在人血浆和肝微粒体中代谢产物鉴定
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摘要
目的研究盐酸丁咯地尔在人体的代谢情况。方法采用UPLC-QTOF/MS法发现并鉴定盐酸丁咯地尔在人血浆和肝微粒体孵化体系中的代谢产物。采用HSS T3 C18色谱柱(100 mm×2.1 mm,1.8μm),以5 mmol·L~(-1)醋酸铵水溶液(含体积分数0.05%的甲酸)(A)-甲醇(B)为流动相梯度洗脱,流速为0.4 m L·min~(-1),采用ESI离子源,正离子模式下检测。结果通过与空白生物样品进行比较,在人血浆和肝微粒体中共发现了丁咯地尔及其24种代谢产物,其中18种为首次发现的代谢产物。根据代谢产物的色谱保留时间、准分子离子及碎片离子等信息,确定并推断了丁咯地尔及其代谢产物的结构,阐明了丁咯地尔在人体的代谢途径,包括去甲基化、氧化、羟基化、硫酸和葡萄糖醛酸结合途径。结论建立了UPLC-QTOF/MS方法研究了丁咯地尔在人体的代谢情况,为其化学结构类似药物和候选化合物的代谢研究提供依据。
Objective To understand the metabolism of buflomedil hydrochloride in human. Methods An ultra performance liquid chromatography coupled with quanrupole time of flight mass spectrometry( UPLCQTOF/M S) was developed to identify the metabolites of buflomedil in human plasma and human liver microsomes. Chromatographic separation was performed on a HSS C_(18)( 100 mm × 2. 1 mm,1. 8 μm) column using gradient elution with mobile phase consisting of 5 mmol·L~(-1) ammonium acetate containing 0. 1%( φ)formic acid( A) and acetonitrile containing 0. 1%( φ) formic acid( B) at a flowrate of 0. 4 m L·min~(-1). A M icromass Q-TOF Premier mass spectrometer coupled to an electrospray ionization( ESI) source was operated in positive ion mode. Results A total of 24 metabolites were identified in human plasma and human liver microsomes by comparing the negative control samples,18 of which were first discovered metabolites.According to the retention time,quasi-molecular ion and fragment ions,the structures of buflomedil and its metabolites were identified. The metabolism pathways in human were clarified,including demethylation,oxidation,hydroxylation,sulfation and glucuronide conjugation pathway. Conclusions The metabolic profile of buflomedil hydrochloride in human was established by UPLC-QTOF/M S,which provided useful information for the metabolic studies of the buflomedil structure similar drugs and candidate compounds.
Objective To understand the metabolism of buflomedil hydrochloride in human. Methods An ultra performance liquid chromatography coupled with quanrupole time of flight mass spectrometry( UPLCQTOF/M S) was developed to identify the metabolites of buflomedil in human plasma and human liver microsomes. Chromatographic separation was performed on a HSS C_(18)( 100 mm × 2. 1 mm,1. 8 μm) column using gradient elution with mobile phase consisting of 5 mmol·L~(-1) ammonium acetate containing 0. 1%( φ)formic acid( A) and acetonitrile containing 0. 1%( φ) formic acid( B) at a flowrate of 0. 4 m L·min~(-1). A M icromass Q-TOF Premier mass spectrometer coupled to an electrospray ionization( ESI) source was operated in positive ion mode. Results A total of 24 metabolites were identified in human plasma and human liver microsomes by comparing the negative control samples,18 of which were first discovered metabolites.According to the retention time,quasi-molecular ion and fragment ions,the structures of buflomedil and its metabolites were identified. The metabolism pathways in human were clarified,including demethylation,oxidation,hydroxylation,sulfation and glucuronide conjugation pathway. Conclusions The metabolic profile of buflomedil hydrochloride in human was established by UPLC-QTOF/M S,which provided useful information for the metabolic studies of the buflomedil structure similar drugs and candidate compounds.
引文
[1]BRIGUGLIOF S,MONDELLO M R,GALLUZZO M,et al.Protective effect of buflomedil in a rat model of moderatecerebralischemia[J].Arzneimittelforschung Drug Research,2005,55(8):437-442.
[2]TANG J R,WU L,SU J H,et al.5-Vasoactive agent buflomedil up-regulated expression of vascular endothelial growth factor in a rat model of sciatic nerve crush injury[J].Ind J Pharmacol,2012,44(4):480-484.
[3]AKHTARN N,ARKVANSHI S,BHATTACHARYA S S,et al.Preparation and evaluation of a buflomedil hydrochloride niosomal patch for transdermal delivery[J].J Liposome Res,2015,25(3):191-201.
[4]颜建辉,黄丽娟,刘剑萍,等.强力定眩片联合丁咯地尔治疗椎-基底动脉供血不足眩晕效果观察[J].临床医学专辑,2015,11(1):1413-1415.
[5]吕国伟,梁阿铭,韩义娜.丁咯地尔预防蛛网膜下腔出血后脑血管痉挛效果观察及其机制探讨[J].山东医药,2016,56(14):82-84.
[6]裴大勇.丁咯地尔用于慢性脑供血不足的临床治疗分析[J].中国医药指南,2016,14(13):145.
[7]ALBERTI A,VALENTI S,GALLO F,et al.Acute buflomedil intoxication:a life-threatening condition[J].Intensive Care Medicine,1994,20:219-221.
[8]VANDEMERGEL X,BISTON P,LENEARTS L,et al.Buflomedil poisoning a potentially life-threatening intoxication[J].Intensive Care Medicine,2000,26:1713.
[9]梁秀琳,毛庆,侍海存,等.丁咯地尔导致不良反应分析[J].中国医药指南,2010,8(15):63-64.
[10]BUCOLO C,LONGO L,CAMILIERI G,et al.Safety profile assessment of buflomedil:an overview of adverse reactions between 1975 and 2011[J].Pharmacoepiddemiology and Drug Safety,2012,21:1190-1196.
[11]王琼,王海芸,许巧巧,等.盐酸丁咯地尔的临床应用和不良反应[J].中国现代医生,2012,50(31):24-26.
[12]US.Food and Drug Administration.Drugs@FDA:FDA Approved Drug Products[EB/OL].[2016-06-21]http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&Appl No=019002
[13]李艾芳,王旗.基于药物代谢的药物毒性研究方法[R].北京:中国药物毒理学年会,2011:154-155.
[14]王薇,杨亚楠,马晓敏,等.短刺小克银汉霉AS 3.15菌株对丁咯地尔的代谢转化[J].药学学报,2012,47(7):934-940.
[15]杨亚楠.盐酸丁咯地尔的人体生物等效性和药物代谢研究[D].沈阳:沈阳药科大学,2011.
[2]TANG J R,WU L,SU J H,et al.5-Vasoactive agent buflomedil up-regulated expression of vascular endothelial growth factor in a rat model of sciatic nerve crush injury[J].Ind J Pharmacol,2012,44(4):480-484.
[3]AKHTARN N,ARKVANSHI S,BHATTACHARYA S S,et al.Preparation and evaluation of a buflomedil hydrochloride niosomal patch for transdermal delivery[J].J Liposome Res,2015,25(3):191-201.
[4]颜建辉,黄丽娟,刘剑萍,等.强力定眩片联合丁咯地尔治疗椎-基底动脉供血不足眩晕效果观察[J].临床医学专辑,2015,11(1):1413-1415.
[5]吕国伟,梁阿铭,韩义娜.丁咯地尔预防蛛网膜下腔出血后脑血管痉挛效果观察及其机制探讨[J].山东医药,2016,56(14):82-84.
[6]裴大勇.丁咯地尔用于慢性脑供血不足的临床治疗分析[J].中国医药指南,2016,14(13):145.
[7]ALBERTI A,VALENTI S,GALLO F,et al.Acute buflomedil intoxication:a life-threatening condition[J].Intensive Care Medicine,1994,20:219-221.
[8]VANDEMERGEL X,BISTON P,LENEARTS L,et al.Buflomedil poisoning a potentially life-threatening intoxication[J].Intensive Care Medicine,2000,26:1713.
[9]梁秀琳,毛庆,侍海存,等.丁咯地尔导致不良反应分析[J].中国医药指南,2010,8(15):63-64.
[10]BUCOLO C,LONGO L,CAMILIERI G,et al.Safety profile assessment of buflomedil:an overview of adverse reactions between 1975 and 2011[J].Pharmacoepiddemiology and Drug Safety,2012,21:1190-1196.
[11]王琼,王海芸,许巧巧,等.盐酸丁咯地尔的临床应用和不良反应[J].中国现代医生,2012,50(31):24-26.
[12]US.Food and Drug Administration.Drugs@FDA:FDA Approved Drug Products[EB/OL].[2016-06-21]http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&Appl No=019002
[13]李艾芳,王旗.基于药物代谢的药物毒性研究方法[R].北京:中国药物毒理学年会,2011:154-155.
[14]王薇,杨亚楠,马晓敏,等.短刺小克银汉霉AS 3.15菌株对丁咯地尔的代谢转化[J].药学学报,2012,47(7):934-940.
[15]杨亚楠.盐酸丁咯地尔的人体生物等效性和药物代谢研究[D].沈阳:沈阳药科大学,2011.