超高效液相色谱-串联质谱法测定去氢骆驼蓬碱衍生物DH-330血药浓度及其在大鼠体内的药动学评价
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篇名: 超高效液相色谱-串联质谱法测定去氢骆驼蓬碱衍生物DH-330血药浓度及其在大鼠体内的药动学评价
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摘要: 目的:建立大鼠血浆中去氢骆驼蓬碱衍生物DH-330的测定方法,并对大鼠灌胃DH-330后的药动学行为进行评价。方法:以替硝唑为内标,血浆样品以乙腈沉淀蛋白处理后,采用超高效液相色谱-串联质谱法测定血药浓度。色谱分析采用色谱柱为Waters ACQUITY BEH C18(50 mm×2.1 mm,1.7 μm),流动相为乙腈-甲醇-0.5%甲酸水溶液(15 ∶ 55 ∶ 30,V/V/V),流速为0.4 mL/min,柱温为30 ℃,进样量为5 μL;质谱分析采用电喷雾电离源,正离子扫描,离子源温度为124 ℃,DH-330检测质荷比(m/z)为335.8→334.8,内标m/z为247.0→81.0。取6 只Wistar大鼠,灌胃DH-330混悬液(50 mg/kg),分别于给药前(0 h)及给药后0.25、0.5、1、2、4、6、8、12、24 h时于大鼠眼底静脉丛采血,测定DH-330血药浓度并绘制血药浓度-时间曲线,并采用Kinetica 5.0软件计算其药动学参数。结果:DH-330血药浓度的线性范围为25.05~2 004 ng/mL(r=0.999 8),定量下限为25.05 ng/mL;日内、日间精密度RSD均小于10%;准确度相对误差(RE)为-9.76%~4.55%,提取回收率大于85%(RSD<5%);稳定性RE为-2.53%~2.29%;不受基质效应或进样残留效应的影响。大鼠灌胃DH-330后达峰浓度为(1 162.43±241.72)ng/mL,药-时曲线下面积为(3 242.93±652.31)ng·h/mL,半衰期为(1.93±0.61)h,平均滞留时间为(3.23±0.30)h,清除率为(16.80±5.30)L/(h·kg),稳态表观分布容积为(54.78±19.64)L/kg。结论:本研究建立的方法具有操作简便,专属性强,灵敏度、精密度及回收率高等优点,可用于大鼠血浆中DH-330血药浓度的测定。大鼠灌胃给药后,DH-330的半衰期短,吸收迅速,表观分布容积大,表明其具有高的亲脂性,可能主要集中分布于组织中。
ABSTRACT: OBJECTIVE: To establish a method for the determination of harmine derivative DH-330 in rat plasma and to use it for pharmacokinetic behavior evaluation of DH-330 in rats after intragastric administration. METHODS: Using tinidazole as internal standard, after pre-treatment of acetonitrile precipitated protein, UPLC-MS method was adopted to determine the plasma concentration of DH-330. UPLC analysis was performed on Waters ACQUITY BEH C18 column (50 mm×2.1 mm,1.7 μm) with mobile phase consisted of acetonitrile-methanol-0.5% formic acid aqueous solution(15 ∶ 55 ∶ 30, V/V/V) at flow rate of 0.4 mL/min, while the column temperature was 30 ℃, and sample size was 5 μL. MS analysis was conducted by electrospray ionization source, positive ion scanning, ion source temperature at 124 ℃, DH-330 detection of mass to charge ratio (m/z) of 335.8→334.8, and internal standard m/z of 247.0→81.0. Six Wistar rats were given DH-330 suspension(50 mg/kg) intragastrically. Blood samples were collected from fundus venous plexus capillary before administration (0 h) and 0.25,0.5,1,2,4,6,8,12,24 h after administration. Plasma concentration of DH-330 was determined and plasma concentration-time curves were drawn. Pharmacokinetic parameters were calculated by using Kinetica 5.0 software. RESULTS: The linear ranges of DH-330 were 25.05-2 004 ng/mL(r=0.999 8),and the limits of quantitation was 25.05 ng/mL. RSDs of intra-day and inter-day were all less than 10%. The accuracy RE was -9.76% to 4.55%. The extraction recovery was higher than 85%(RSD<5%). Stability RE was -2.53% to 2.29%. They were not affected by matrix effect or residual effect of injection. The pharmacokinetic parameters of DH-330 in rats after intragastric administration included that cmax was (1 162.43±241.72)ng/mL,AUC0-∞ was (3 242.93±652.31)ng·h/mL,t1/2 was (1.93±0.61)h, MRT was (3.23±0.30)h,CL was (16.80±5.30)L/h·kg, Vss was (54.78±19.64)L/kg. CONCLUSIONS: The established method is simple, specific, sensitive, precise and recovery, which can be used for the plasma concentration determination of DH-330 in rats. DH-330 has short half-life, rapid absorption and large apparent distribution volume after intragastric administration in rats, which indicates that it has high lipophilicity and may be mainly distributed in tissues.
期刊: 2019年第30卷第12期
作者: 高惠静,阿尔斯兰·艾合买提,许兆辉,范文玺,陈国儒,赵军
AUTHORS: GAO Huijing,Arslan·Ahmat,XU Zhaohui,FAN Wenxi,CHEN Guoru,ZHAO Jun
关键字: 去氢骆驼蓬碱衍生物;DH-330;超高效液相色谱-串联质谱法;血药浓度;药动学;大鼠
KEYWORDS: Harmine derivative; DH-330; UPLC-MS; Plasma concentration; Pharmacokinetics; Rats
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