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-中国药房

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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本月下载数：	9 次

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