CN104352632B - 一种柏艾胶囊作为肝转运体抑制剂的应用 - Google Patents

一种柏艾胶囊作为肝转运体抑制剂的应用 Download PDF

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CN104352632B
CN104352632B CN201410645693.XA CN201410645693A CN104352632B CN 104352632 B CN104352632 B CN 104352632B CN 201410645693 A CN201410645693 A CN 201410645693A CN 104352632 B CN104352632 B CN 104352632B
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王海盛
闫利颖
蔡正军
龙娜
张素行
张飞鹏
张科之
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Beijing Haiyan Pharmaceutical Industry Co Ltd Yangzijiang Pharmaceutical Ind
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Abstract

本发明涉及一种柏艾胶囊作为肝转运体抑制剂的应用。具体的,柏艾胶囊对肝转运体(包括摄取型转运体和外排型转运体)具有抑制作用,从而柏艾胶囊可以与西药联合用药以预防或防治疾病,例如柏艾胶囊当作肝转运体抑制剂而与厄贝沙坦联合使用以防治高血压。

Description

一种柏艾胶囊作为肝转运体抑制剂的应用
技术领域
本发明涉及一种柏艾胶囊作为肝转运体抑制剂的应用。
背景技术
转运体是位于细胞膜上的功能性膜蛋白,在胃肠道、肝脏、血脑屏障和肾脏等重要器官都有广泛表达,直接影响了大多数内源性物质、外源性化学异物或药物的吸收、分布、代谢和毒性作用。而其中的肝转运体在药物肝胆转运中起着重要作用,它将药物摄取进入肝脏,在肝脏经过一定的代谢转化,最终将其经胆汁排至肝外。其中摄取型的肝转运体OATP1B1、OATP1B3和外排型转运体MRP2、BSEP已成为美国FDA和欧洲EMA规定的新药申报的必做的实验项目。而摄取型的NTCP则是胆酸的肝胆循环的必经环节。
近年来,临床上药物药物相互作用(DDI)的发生日益引起国际关注,美国食品药品监督管理局(FDA)已将药物临床药物相互作用发生可能性的评价作为新药报批的必要文件之一。而以往药物间相互作用的研究多着重于药物代谢酶(如细胞色素P450酶)的诱导或抑制,但随着对转运体研究的不断深入,发现很多药物间的相互作用是由转运体的诱导、抑制或基因多态性所致。因此基于转运体介导的药物相互作用日益成为新药研发和审批的焦点和热点。其中由肝转运体介导的药物相互作用成为重中之重。
目前,临床上中西药联合用药日趋普遍,其效果已得到医学界的普遍认可。中西药联合可以协同增效,降低毒副作用,降低用药剂量,减少用药禁忌,扩大适应范围。但由于中药的化学成分和药理作用十分复杂,中西药联合使用不当,亦会降低疗效,增加副作用或引起药源性疾病,严重的甚至危及生命,所以要同时规避和预防药物配伍禁忌。在用药安全备受关注的大背景下,中药引起的药物相互作用也逐渐开展起来,特别是对于转运体和代谢酶的诱导和抑制作用。
发明内容
本发明所要解决的技术问题是提供一种柏艾胶囊作为肝转运体的应用,柏艾胶囊对肝转运体具有有效的抑制作用。
本发明解决上述技术问题所采用的技术方案为:一种柏艾胶囊作为肝转运体抑制剂的应用。
其中,所述柏艾胶囊包括如下重量份数的组分:
其中,所述肝转运体包括摄取型转运体和外排型转运体。
其中,所述摄取型转运体为为NTCP、OATP或OCT。
其中,所述外排型转运体为MDR1、MDP2或BSEP。
一种柏艾胶囊作为肝转运体抑制剂与厄贝沙坦联合使用在防治高血压上的应用。
与现有技术相比,本发明的优点在于:柏艾胶囊可充当肝转运体抑制剂,其对肝转运体(包括摄取型转运体和外排型转运体)具有抑制作用。从而柏艾胶囊可以与西药联合用药以预防或防治疾病,例如柏艾胶囊当作肝转运体抑制剂而与厄贝沙坦联合使用以防治高血压,其中,柏艾胶囊可增加外排底物型西药的吸收,从而增强厄贝沙坦的药效,同时有效抑制了厄贝沙坦的肝摄取,从而减低了厄贝沙坦的肝清除。因此,本发明为柏艾胶囊与其他西药联合用药提供了依据。
附图说明
图1为本发明实施例柏艾胶囊对肝摄取型转运体底物的抑制作用;
图2为本发明实施例柏艾胶囊对肝摄取厄贝沙坦的抑制作用;
图3为本发明实施例不同抑制剂对肝摄取厄贝沙坦的抑制作用;
图4为本发明实施例三明治培养的人体肝细胞中厄贝沙坦Km和Vmax的摄取量;
图5为本发明实施例柏艾胶囊对人体肝细胞牛胆磺酸钠的胆管外排的抑制作用。
具体实施方式
以下结合附图实施例对本发明作进一步详细描述。
本实施例中提及的浓度是指在三明治培养的人肝细胞或大鼠肝细胞中的浓度。
柏艾胶囊可充当肝转运体抑制剂,其对肝转运体具有有效的抑制作用。柏艾胶囊的主要成分包括如下重量份数的组分:
侧柏叶 20~30%;
地黄 20~30%;
艾叶 20~30%;
荷叶 20~30%。
本实施例具体采用的是由扬子江药业集团有限公司生产的批次为13080642的柏艾胶囊,该柏艾胶囊各组分的配比在上述范围内。
肝转运体包括负责将内外源性物质摄入细胞内的摄取型转运体,其中包含有机阴离子转运多肽(organic anion transporting polypeptides,OATP)、有机阴离子转运体(organic anion transporter,OAT)、有机阳离子转运体(organic cation transporter,OCT)、Na+-牛磺胆酸共转运多肽(Na+-taurocholate cotransporting polypeptide,NTCP)和外排型转运体主要是多药耐药蛋白(multi-drug resistance protein,MDR)[其中MDR1又称为P-糖蛋白(P-glycoprotein,P-gp)]、多药耐药相关蛋白(multi-drug resistance-associated protein,MRP)[其中,MPR2为毛细血管多专属性有机阴离子转运体]、乳腺癌耐药相关蛋白(breast cancer resistance protein,BCRP)以及肝脏胆盐外排泵(bile saltexport pμMp,BSEP)等。
而柏艾胶囊具体对摄取型转运体NTCP、OATP、OCT和外排型转运体MDR1、MRP2和BSEP都有有效的抑制作用,特别是对OATP和MDR1的抑制作用最强。
研究肝转运体的方法包括原代培养的肝细胞模型、动物模型、表达转运体的膜囊模型或稳转细胞株等。其中,三明治培养的人肝细胞模型是最经典、最可靠和应用最广泛的模型,它可以最大限度的模拟人肝细胞正常生理状况,可避免种属差异,近年来已成为研究药物相互作用包括代谢酶介导和转运体介导的相互作用的黄金标准。
长期以来,由于柏艾胶囊作为中药制剂,成分复杂,对药物间相互作用的影响不明确,包括对代谢酶和转运体的作用。本实施例采用体外三明治培养的人肝细胞模型和大鼠肝细胞模型,从细胞水平上考察柏艾胶囊对肝转运体的作用。本实施例主要从以下三方面来验证柏艾胶囊(厂商:扬子江药业集团有限公司,生产批次:13080642)对肝摄取型转运体的抑制作用:
1、利用三明治培养的人肝细胞模型和最重要的三个摄取型转运体(NTCP、OATP和OCT)对应的底物,证明柏艾胶囊是肝摄取型转运体的抑制剂。
由表1和图1所示的测试结果可知,柏艾胶囊对三种摄取型转运体都有抑制作用,其中对OATP的作用最强(半数抑制浓度IC50=0.06mg/mL);并且对三个不同供体(FY016、ZS007和ZS033)的人肝细胞上的转运体的作用无明显差异。
表1.柏艾胶囊对摄取型转运体的抑制效果
表1中,d5-taurocholate为氘代牛胆磺酸,Rosuvastatin为瑞舒伐他汀,MPP为经典底物——1-甲基-4-苯基吡啶离子。
图1中,a的底物为Rosuvastatin,b的底物为d5-taurocholate,c的底物为MPP。
2、利用三明治培养的人肝细胞模型,证明厄贝沙坦为肝转运体的底物以及柏艾胶囊对厄贝沙坦的抑制作用。
表2和图2至图4显示,厄贝沙坦为肝转运体的底物(Vmax=1399pmol/mg protein/min,Km=38.69μM)。并在已知的肝转运体抑制剂作用下细胞摄取减低,且无特异性,说明厄贝沙坦的肝主动摄取可经过多种途径,包括NTCP、OATP和OCT。而柏艾胶囊亦可有效抑制厄贝沙坦的肝摄取(IC50=0.4mg/mL),从而减低厄贝沙坦的肝清除。
图3中,a为利福霉素,b的抑制剂为环孢素A,c的抑制剂为维拉帕米。
表2.柏艾胶囊对厄贝沙坦的抑制作用
3、利用三明治培养的人肝细胞和大鼠肝细胞为模型,研究柏艾胶囊对外排型转运体的抑制作用。
表3和图5显示,2mg/mL的柏艾胶囊对人肝细胞上的外排转运体BSEP有一定的抑制作用,牛胆磺酸钠的胆管外排百分比(BEI)从50%降到37%。而在大鼠肝细胞的胆管外排实验中也得到了相似的结论,从下表中2mg/mL的柏艾胶囊将牛胆磺酸钠的胆管外排百分比(BEI)从60%降到40%,且对其他两个外排转运体MDR1和MRP2也有明显抑制作用,特别是对由MDR1介导的MPP的外排可实现完全抑制。对MRP2介导的瑞舒伐他汀的外排也有部分抑制,BEI从46%降到21%。
表3.柏艾胶囊对外排型转运体的抑制作用
表3中,TCD5为氘代牛胆磺酸。
基于上述对柏艾胶囊对肝转运体具有抑制作用的验证,柏艾胶囊可以与西药联合用药以预防或防治疾病,例如与厄贝沙坦联合用药以防治高血压。
综合以上数据,在以体外的三明治培养的人肝细胞和大鼠肝细胞为模型的摄取和外排实验中,柏艾胶囊对肝转运体包括摄取型的NTCP、OATP、OCT和外排型的MDR1、MRP2和BSEP都有抑制作用,特别是OATP和MDR1的作用最强。因此,柏艾胶囊可作为一种新型的肝转运体的抑制剂。
以上内容仅为本发明的较佳实施例,对于本领域的普通技术人员,依据本发明的思想,在具体实施方式及应用范围上均会有改变之处,本说明书内容不应理解为对本发明的限制。

Claims (2)

1.一种柏艾胶囊作为制备肝转运体抑制剂的应用,所述肝转运体包括摄取型转运体和外排型转运体,所述摄取型转运体为NTCP、OATP或OCT,所述外排型转运体为MDP2或BSEP;
其中,所述柏艾胶囊的中药原料由如下重量百分数的组分组成:
2.一种权利要求1所述的柏艾胶囊作为肝转运体抑制剂与厄贝沙坦联合使用在制备防治高血压药物的应用。
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