五酯胶囊对大鼠体内甲磺酸阿帕替尼药动学行为的影响
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篇名: 五酯胶囊对大鼠体内甲磺酸阿帕替尼药动学行为的影响
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摘要: 目的:建立测定大鼠血浆中甲磺酸阿帕替尼浓度的方法,并考察单次和多次给予五酯胶囊对大鼠体内甲磺酸阿帕替尼药动学行为的影响。方法:采用液相色谱-串联质谱法(LC-MS/MS)检测大鼠血浆中甲磺酸阿帕替尼的浓度。以卡马西平为内标,色谱柱为Waters XBridge BEH C18,流动相为乙腈-0.1%甲酸溶液(45 ∶ 55,V/V),流速为0.3 mL/min,柱温为40 ℃,进样器温度为15 ℃,进样量为2 μL;采用电喷雾离子源,以多反应监测模式进行正离子扫描,用于定量分析的离子对质荷比分别为398.1→212.1(甲磺酸阿帕替尼)、237.2→194.2(内标)。将大鼠随机分为对照组Ⅰ、观察组Ⅰ、对照组Ⅱ、观察组Ⅱ,每组6只。对照组Ⅰ大鼠单次灌胃甲磺酸阿帕替尼(50 mg/kg,下同);观察组Ⅰ大鼠灌胃五酯胶囊(450 mg/kg,下同),10 min后再灌胃甲磺酸阿帕替尼;对照组Ⅱ大鼠灌胃生理盐水,每日1次,连续7 d后,再单次灌胃甲磺酸阿帕替尼;观察组Ⅱ大鼠灌胃五酯胶囊,每日1次,连续7 d后,再单次灌胃甲磺酸阿帕替尼。分别于灌胃甲磺酸阿帕替尼后0.25、0.5、1.0、2.0、2.5、3.0、4.0、6.0、8.0、12.0、24.0 h时自大鼠眼内眦静脉丛采血进行测定。分别采用DAS 2.1软件和t检验计算和比较各组大鼠的药动学参数。结果:甲磺酸阿帕替尼检测血药浓度的线性范围为2~2 000 ng/mL,定量下限为2 ng/mL;日内、日间RSD均小于10%,准确度为94.93%~104.68%;基质效应不影响待测物的定量分析。与对照组Ⅰ比较,观察组Ⅰ大鼠的cmax、AUC0-24 h、AUC0-∞均显著升高,CLZ显著降低(P<0.05);与对照组Ⅱ比较,观察组Ⅱ大鼠的AUC0-24 h、AUC0-∞均显著升高,CLZ显著降低(P<0.05);与观察组Ⅰ比较,观察组Ⅱ大鼠的AUC0-24 h、AUC0-∞均显著降低(P<0.05)。结论:本研究建立的LC-MS/MS法灵敏度高、专属性强,可用于大鼠血浆中甲磺酸阿帕替尼浓度的测定及药动学研究。五酯胶囊可影响大鼠体内甲磺酸阿帕替尼的药动学行为,且多次给予五酯胶囊的影响弱于单次给药。
ABSTRACT: OBJECTIVE: To establish a method for the concentration determination of apatinib mesylate in plasma of rats, and to investigate the effects of single and multiple administration of Wuzhi capsules on the pharmacokinetic behavior of apatinib mesylate in rats. METHODS:  LC-MS/MS method was used to detect the plasma concentration of apatinib mesylate in rats. Using carbamazepine as internal standard, the determination was performed on Waters XBridge BEH C18 column with mobile phase consisted acetonitrile-0.1% formic acid solution (45 ∶ 55,V/V) at the flow rate of 0.3 mL/min. The column temperature was 40 ℃. The temperature of injector was 15 ℃, and the sample size was 2 μL. ESI was used for positive ion scanning in MRM mode. The ion pairs m/z used for quantitative analysis were 398.1→212.1 (apatinib mesylate) and  237.2→194.2 (internal standard). The rats were randomly divided into control group Ⅰ, observation group Ⅰ, control group Ⅱ, observation group Ⅱ, with 6 rats in each group. Control group Ⅰ were given single administration of apatinib mesylate intragastrically (50 mg/kg, similarly hereinafter). Observation group Ⅰ was given Wuzhi capsules intragastrically (450 mg/kg, similarly hereinafter), and then 10 min later given apatinib mesylate intragastrically. Control group Ⅱ was given normal saline intragastrically, once a day, for consecutive 7 d, and then were given single administration of apatinib mesylate. Observation group Ⅱ was given Wuzhi capsules intragastrically, once a day, for consecutive 7 d, and then 10 min later were given single administration of apatinib mesylate. The blood samples were collected from intraocular canthus vein plexus and determined 0.25, 0.5, 1.0, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0 h after intragastric administration, respectively. Pharmacokinetic parameters were apatinib mesylate were calculated and compared among those groups by using DAS 2.1 software and t-test. RESULTS: The linear range of apatinib mesylate were 2-2 000 ng/mL. The lower limit of quantitation was 2 ng/mL. RSDs of intra- day and inter-day were all lower than 10%, and the accuracy were 94.93%-104.68%. Matrix effect did not affect the quantitative analysis of the substance to be measured. Compared with control group Ⅰ, cmax, AUC0-24 h and AUC0-∞ of observation group Ⅰ were increased significantly, CLZ was decreased significantly (P<0.05). Compared with control group Ⅱ, AUC0-24 h and AUC0-∞ of observation group Ⅱ were increased significantly, and CLZ was decreased significantly (P<0.05). Compared with observation group Ⅰ, AUC0-24 h and AUC0-∞ of observation group Ⅱ were decreased significantly (P<0.05). CONCLUSIONS: Established LC-MS/MS method is sensitive and specific, and can be used for the concentration determination of apatinib mesylate in plasma of rats. Wuzhi capsules can influence in vivo pharmacokinetic behavior of apatinib mesylate in rats. The effect of multiple administration of Wuzhi capsules is weaker than that of single administration.
期刊: 2019年第30卷第12期
作者: 李亚静,刘洪涛,王祁民,李颖,董占军
AUTHORS: LI Yajing,LIU Hongtao,WANG Qimin,LI Ying,DONG Zhanjun
关键字: 甲磺酸阿帕替尼;五酯胶囊;药动学;液相色谱-串联质谱法;大鼠
KEYWORDS: Apatinib mesylate; Wuzhi capsules; Pharmacokinetics; LC-MS/MS; Rats
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