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 点击下载
| 论文标题： | 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 |
| 英文标题： | |
| 中文摘要： | 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。 |
| 英文摘要： | 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 |
| 英文作者： | 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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| 文件大小： | 619.60Kb |
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