基于代谢酶的威麦宁胶囊与多潘立酮相互作用研究

发布时间：2023-03-09 16:12

  本文选题：威麦宁胶囊　切入点：原花青素B2　出处：《南京中医药大学》2014年硕士论文　论文类型：学位论文

【摘要】：威麦宁胶囊为金荞麦干燥根茎中含有的抗癌活性成份,经醇提水沉方法提取后制得的国家二类中药新药保护品种。具有清热解毒、活血化瘀、驱邪扶正等作用。临床上主要用于不适宜放、化疗肺癌患者的治疗,可增加患者的免疫力。 由于威麦宁胶囊是刚上市药品,临床研究相对较少。但已经有相关的文献报道了从金荞麦的根茎中能够提取出抗癌活性物质,且含量较高。威麦宁胶囊又是从金荞麦根茎中提取制成的抗癌药物,中国药典中已将表儿茶素的含量作为金荞麦的质量标准,因此本课题选择根茎中含量较高的抗癌活性成份原花青素B2和表儿茶素作为研究对象进行研究,为威麦宁胶囊临床用药,以及后期的科研研究提供一些数据支持。 为了测定威麦宁胶囊中原花青素B2、表儿茶素的含量,采用高效液相色谱法,ZorbaxSB-C18色谱柱,乙腈-0.04%磷酸水溶液为流动相,1.0mL/min的流速,检测波长为280nm,柱温30℃,进样量10μL,由于原花青素B2和表儿茶素极性相近,所以采用梯度洗脱,使两峰拉开。结果显示,原花青素B2和表儿茶素的标准曲线分别为A原花青素B2=7047.3C-1066(r=0.9998),A表儿茶素=7321.9C-601.43(r=0.9999),加样回收率分别为93.56%(RSD4.36%)、99.34%(RSD4.14%)。威麦宁胶囊3个批次中原花青素B2、表儿茶素的平均含量分别为1.44mg/粒、0.96mg/粒。因此,威麦宁胶囊三个批次中原花青素B2和表儿茶素的含量相近。该方法简便、准确、重复性好,可为威麦宁胶囊提供质量控制方法,为后期实验提供含量的数据。 采用高效液相色谱法检测原花青素B2和表儿茶素药物浓度测定方法,并通过平衡透析法测定二者在体外血浆蛋白结合率。结果显示,在低、中、高3个浓度下,原花青素B2在人和大鼠体外血浆中的蛋白结合率分别为(44.21±2.80)%、(52.60±1.92)%、(48.11±3.09)%和(82.88±3.24)%、(80.19±2.53)%、(79.95±3.19)%。表儿茶素在人和大鼠体外的血浆中的蛋白结合率分别为(47.12±2.85)%、(55.03±2.47)%、(43.69±1.53)%和(74.74±4.28)%、(75.63±3.25)%、(73.82±3.63)%。HPLC法简便、可靠、稳定。原花青素B2和表儿茶素在大鼠、人体外血浆属中等结合型药物,无明显的浓度依赖性,但原花青素B2和表儿茶素与大鼠的血浆蛋白结合率高于人的血浆蛋白结合率,说明存在种属差异性。 采用Cocktail探针药物法探讨了威麦宁胶囊对大鼠体内六种CYP450酶活性的影响,为威麦宁胶囊临床可能联合用药时相互作用提供依据。分别选用甲苯磺丁脲(CYP2C6)、氯唑沙宗(CYP2E1)、茶碱(CYP1A2)、眯达唑仑(CYP3A2)、奥美拉唑(CYP2D1)、右美沙芬(CYP2D2)作为六个亚型酶的探针底物。每日早晨灌胃临床等剂量的威麦宁胶囊,采用液质联用色谱法(LC-MS/MS)测定给药前后大鼠体内六种混合探针的血药浓度,计算药动学参数。结果显示,威麦宁胶囊连续给药2周后,与给药前相比,奥美拉唑、咪达唑仑(p0.05)和右美沙芬代谢明显减慢,茶碱、甲苯磺丁脲、氯唑沙宗的代谢无显著性差异。因此,威麦宁胶囊对大鼠体内CYP2D1、CYP3A2、CYP2D2(相对应的人体内的CYP2C19、CYP3A4、CYP2D6)三个亚型酶有抑制作用,对CYP1A2、CYP2C6、CYP2E1(相对应人体内的CYP1A2、CYP2C9、CYP2E1)三个亚型酶的活性无显著影响。 为了研究威麦宁胶囊对多潘立酮药动学的影响。选用8只大鼠连续10天灌胃威麦宁胶囊(1.6g/kg),并在给威麦宁胶囊前一天和最后一天灌胃多潘立酮片(4mg/kg),用液质联用色谱法(LC-MS/MS)测定大鼠体内多潘立酮的血药浓度,计算药动学参数,并比较大鼠给药前后主要药动学参数的差异性。结果显示,威麦宁胶囊给药后,多潘立酮的Tmax、 Cmax、AUC0-t值较没有给威麦宁胶囊时有明显的增高(P0.05),其他药动学参数无显著性差异。因此,威麦宁胶囊连续给药后,致使多潘立酮的血药浓度增加,可能会导致多潘立酮在体内的药物蓄积,从而加重多潘立酮对心脏等毒副作用,同时也验证了威麦宁胶囊对大鼠CYP3A2酶(人的CYP3A4酶)有影响。

【学位级别】：硕士

[Abstract]:Weimaining capsules containing gold buckwheat dried rhizome of the active ingredients of anticancer, by ethanol extraction method after prepared two kind of national medicine to protect species. With detoxification, blood stasis, etc. Clinical Fuzheng evil is mainly used for the treatment of patients with lung cancer, chemotherapy, patients can increase immunity.
Because of weimaining capsules are just listed drugs, clinical research is relatively small. But there have been reports from the golden buckwheat rhizome can extract anti-cancer active substances, and the content is high. Weimaining capsules and anticancer drugs made from buckwheat rhizome extract in the Chinese Pharmacopoeia has content epicatechin as the quality standard of F.cymosum, so the high content of active ingredients in the roots of anticancer procyanidin B2 and epicatechin as the research object, for the clinical use of weimaining capsules, and later the scientific research to provide some data support.
For the determination of weimaining capsules of procyanidin B2, content of epicatechin, HPLC, ZorbaxSB-C18 column, acetonitrile -0.04% phosphoric acid solution as the mobile phase, the flow rate of 1.0mL/min, the detection wavelength was 280nm, the column temperature of 30 DEG C, sample volume 10 L, because the original anthocyanin and B2 epicatechin is eluted by gradient Their natures are much the same., so, the two peak opened. The results showed that procyanidin B2 and epicatechin standard curve were A B2=7047.3C-1066 (r=0.9998), procyanidin A epicatechin (r=0.9999 =7321.9C-601.43), the recoveries were 93.56% (RSD4.36%), 99.34% (RSD4.14%) weimaining capsules. 3 batches of procyanidin B2, the average content of epicatechin were 1.44mg/ particles, 0.96mg/ particles. Therefore, weimaining capsules three batches of procyanidin B2 and epicatechin content are similar. The method is simple, accurate, reproducible and can be weimaining The capsule provides the quality control method and provides the data for the later experiment.
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