CN114796194B - 来源于桑属植物的da加合物的应用 - Google Patents
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Abstract
本发明公开了来源于桑属植物的DA加合物在制备β‑G抑制剂中的应用，属于医药技术领域。本发明采用混合人粪菌总蛋白和/或组合GUS‑表达菌株和/或纯化GUS蛋白的BGUS活性抑制策略，从中药桑白皮提取物中分离筛选出一系列能较好抑制人BGUSs的DA加合物类成分，其中代表性化合物SGG证实在体内有效缓解伊立替康引起的小鼠肠毒性，在体外、体内模型上均显示广谱的BGUSs抑制特点，还能够降低肠上皮细胞转运子OATP2B1对SN‑38的摄取，这种广谱BGUSs抑制以及双环节(SN‑38肠道再激活和肠道重摄取)阻断的作用特点使其较以单一GUS蛋白筛选的抑制剂具有更大的优越性和临床应用潜力。
Description
技术领域
本发明涉及医药技术领域，具体而言，涉及来源于桑属植物的DA加合物的应用。
背景技术
通过宿主尿苷二磷酸葡萄糖醛酸转移酶(UGTs)催化结合反应，生成葡萄糖醛酸苷是许多内外源性成分(包括药物)在体内的主要代谢途径。通过代谢转化提高产物的极性、促进外来物质排出是机体“排毒”的重要方式。但经胆汁排泄到肠道的葡萄糖醛酸苷类化合物在肠道菌β-葡萄糖醛酸苷酶(BGUSs，E.C.3.2.1.31)作用下水解产生苷元，后者重新吸收，经门静脉又返回肝脏，形成肝肠循环。研究发现，宿主UGTs-肠道菌GUSs轴协调作用，参与大量具有重要生物学功能的内源化合物(如胆红素，甾体类激素如雌激素和雄酮，神经递质如多巴胺、去甲肾上腺素和甲状腺素，血清素、胆汁酸等)以及外源性成分(如药物、食源性或环境来源的致癌物杂环胺、HAA等)的体内处置；BGUSs功能异常造成的内源性分子的代谢稳态失调以及对外源性致癌物的代谢“激活”增强与多种疾病的风险增加密切相关，如一些新生儿或吉尔伯特综合征(Gilbert's syndrome)患者的胆红素的肠肝循环程度显著增加，导致高胆红素血症；肠道微生物对激素类葡萄糖醛酸苷的代谢激活促进激素肠肝循环，与某些激素依赖性癌症的发展相关，如循环雌激素代谢物/母体的高比例与绝经后的雌激素受体阳性乳腺癌的发展相关风险增加有关，而多种雄激素葡萄糖醛酸苷与前列腺癌紧密相关。食源性杂环胺类与结直肠癌(CRC)风险相关。此外，BGUSs介导的去葡萄糖醛酸化也影响多个药物，包括抗癌药物如伊立替康(IRT)、瑞戈非尼等，非甾体类抗炎药如双氯芬酸钠、吲哚美辛、布洛芬、酮洛芬等，止痛药吗啡、免疫抑制剂霉酚酸酯等的肠道局部暴露，是造成临床严重的胃肠道不良反应的重要因素。
结直肠癌(CRC)是世界上第三大最常见和致命的癌症，且呈现年轻化趋势。作为CRC一线治疗药，伊立替康(Irinotecan,IRT)常与其他化疗药或者分子靶向药物联合用于CRC术后化疗。IRT是酯类前药，静脉注射后在肝脏羧基酯酶CES2作用下水解产生SN-38，其抗癌活性比IRT强100-1000倍，通过阻断拓扑异构酶I催化的DNA链的断裂-聚合反应，形成稳定的TOP I-DNA可裂解复合物来抑制TOP I。SN-38在肝脏中被部分代谢为无活性的葡萄糖醛酸苷SN-38G，经胆汁排泄后在肠道被BGUSs水解，产生的SN-38在肠道组织积累导致上皮细胞死亡，引发严重的迟发性腹泻，极大限制了IRT的使用剂量，致使患者因直接危及生命的后遗症或间接调整治疗方案使治疗不足而死亡。在接受IRT治疗的CRC患者血中观察到SN-38水平的再次升高；IRT引起的大鼠肠道组织学损伤程度与各肠段内容物的BGUSs活性相关。虽然抗生素预处理可以改善IRT引起的腹泻和盲肠损伤，但使用广谱抗生素会造成菌群失调，增加艰难梭菌等病原菌感染的风险。发现并发展靶向肠道BGUSs的抑制剂、阻断SN-38的产生及肠肝循环成为IRT减毒增效的新策略。目前，已有数个研究在健康动物体内证实了使用BGUSs抑制剂缓解IRT肠毒性的益处，相同策略也能减缓非甾体类抗炎药包括双氯芬酸等造成的严重消化道不良反应。
β-葡萄糖醛酸苷酶属于糖苷酶家族2的成员，能水解β-D-连接的葡萄糖醛酸苷键。人和动物肠道内的许多微生物都可以产生β-葡萄糖醛酸苷酶，2010年有学者首次证实了抑制肠道菌β-葡萄糖苷酶能缓解伊立替康(Irinotecan,IRT)引起的药源性腹泻，随后关于肠道菌β-葡萄糖醛酸苷酶抑制剂的开发和应用受到了广泛关注。虽然肠道中的β-葡萄糖醛酸苷酶的来源不限于大肠杆菌，但大肠杆菌β-葡萄糖醛酸苷酶(EcoGUS)在人和动物肠道中分布广泛而且又易制备，因此EcoGUS常被作为肠道菌β-葡萄糖醛酸苷酶抑制剂研究的常用筛选工具。然而使用EcoGUS筛选得到的强效抑制剂如阿莫沙平(Amoxapine，AMX)对IRT引起的小鼠肠毒性缓解作用并不理想。如何筛选出具有广谱强效β-葡萄糖醛酸苷酶抑制剂是亟待解决的问题。
最近一些研究报道显示天然黄酮成分抑制BGUSs的潜力。但目前这些由EcoGUS筛选出的天然成分的体外抑制效力普遍不高(IC50>10uM)、对其他BGUSs的抑制作用未见报道，动物体内研究仅见黄芩苷及其含黄芩苷的复方改善IRT不良反应的报道。
鉴于此，特提出本发明。
发明内容
本发明的目的是通过改良的体外筛选系统发现来源于桑属植物的DA加合物作为β-G抑制剂的应用。
第一方面，本发明实施例提供了来源于桑属植物的DA加合物或其药学上可接受的盐在制备β-葡萄糖醛酸苷酶广谱抑制剂中的应用。
第二方面，本发明实施例提供了如前述实施例所述的DA加合物在制备OATP2B1抑制剂中的应用。
第三方面，本发明实施例还提供了如前述实施例所述的DA加合物在制备治疗和/或预防去葡萄糖醛酸化产物在肠道积累从而导致的不良反应或疾病的药物中的应用。
本发明具有以下有益效果:
本发明采用混合人粪菌总蛋白BGUS活性抑制策略，来源于桑属植物的特征性成分DA加合物，被证实在体内有效缓解伊立替康引起的小鼠肠毒性，其不仅在体外、体内模型上显示强效广谱的BGUSs抑制特点，还能够抑制肠上皮细胞对SN-38的摄取。这种广谱的BGUSs抑制以及对SN-38肠道再激活和重新摄取双重阻断的作用特点使其较以单一GUS蛋白筛选的抑制剂具有更大的优越性和临床应用潜力。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为活性导向的桑白皮DA加合物分离路线图；
图2为桑根酮G(Sanggenon G，SGG)和阿莫沙平(AMX)对混合人肠道菌总蛋白(phBGUSs)及纯化菌GUS蛋白的浓度依赖抑制曲线(A)以及SGG(B)和AMX(C)对纯化菌GUS蛋白的抑制类型(Lineweaver-Burk)图；
图3为桑根酮G(SGG)和阿莫沙平(AMX)与EcoGUS，SpasGUS，SagaGUS的分子对接图，其中，非竞争性抑制剂AMX于PNPG存在情况下与蛋白对接，灰色为PNPG；橘色为AMX；浅蓝色为SGG；绿色为残基；
图4为桑根酮G(SGG)和阿莫沙平(AMX)体内抑制GUS酶荧光探针荧光素二-β-D-葡糖苷酸水解活性的小鼠肠道内成像分析；
图5为桑根酮G(SGG)和阿莫沙平(AMX)对伊利替康诱导的小鼠体重降低(A)、生存率(B)、腹泻(C)、空肠和结肠组织损伤(D)及评分(E)的影响；
图6为桑根酮G(SGG)和阿莫沙平(AMX)对伊立替康处理小鼠的粪便菌GUSs酶活性(A)、小肠(B)及结肠(C)组织SN-38蓄积、小肠UGT1A1介导的SN-38的葡萄糖醛酸化活性(D)、小肠OATP2B1蛋白表达(E、F)以及Caco-2细胞摄取SN-38活性(G)的影响；
图7为桑根酮G(SGG)和阿莫沙平(AMX)对大肠杆菌E.coli BL21细胞生长的影响(A)以及SGG对人和菌GUS蛋白的选择性抑制作用(B)。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
Diels-Alder(DA)加合物是由一个活泼双键或叁键的化合物(亲双烯体)与共轭二烯类化合物(双烯体)发生[4+2]的环合反应得到的产物，结构新颖、复杂多样。桑属(MorusLinn)植物中存在大量由黄酮、查耳酮、苯并呋喃类形成的DA加合物，是桑属植物的特征性成分。中药桑白皮(Mori Cortex)为桑科桑(M.alba L.)除去栓皮后的干燥根皮，具有泻肺平喘，行水消肿的功效。
发明人首次通过分子对接分析桑白皮中数十种多酚类成分，发现其特征性DA加合物成分与三种GUS蛋白均具有较高的亲和力；进一步采用phBGUSs活性导向的化合物分离，从桑白皮提取物中获得了一系列DA加合物，均对phBGUSs有较强广谱抑制活性。其中，桑根酮G(Sanggenon，SGG)口服后在较低剂量即显示较强的体内抑制动物肠道BGUSs的作用，能有效缓解IRT在健康小鼠体内诱发的肠毒性，作用优于AMX。
研究还发现，SGG还能显著抑制SN-38转运体有机阴离子转运多肽2B1(OATP2B1)在Caco-2细胞的表达，降低SN-38的肠道摄取。以上结果显示，中药桑白皮中DA加合物可通过抑制SN-38的产生(肠道菌BGUSs抑制)和/或肠道摄取(OATP2B1抑制)有效阻断SN-38的肠道循环，缓解IRT的肠毒性，在干预BGUSs介导的其他药物不良反应或致癌风险中具有较大应用潜力。
为实现本发明的上述目的，特采用以下的技术方案：
第一方面，本发明实施例提供了来源于桑属植物的DA加合物或其药学上可接受的盐在制备β-葡萄糖醛酸苷酶广谱抑制剂中的应用。
在可选的实施方式中，β-葡萄糖醛酸苷酶源自混合人肠道菌、人肠道菌GUS-表达菌株和经表达纯化的人肠道菌GUS蛋白中的至少一种。
由于大肠杆菌β-葡萄糖醛酸苷酶(EcoGUS)广泛分布于人和动物肠道内且易于异源表达，多数研究使用EcoGUS筛选和评估BGUSs抑制剂。然而，人肠道微生物表达数百种不同序列和结构的BGUSs，具有较高的底物重叠性和功能冗余性以及不同的抑制倾向，仅使用单一的细菌BGUS远不足以预测不同微生物来源的BGUSs在特定水解反应中的贡献并针对性设计高选择性/强效抑制剂进行干预。如用EcoGUS筛选得到的强效抑制剂阿莫沙平(Amoxapine，AMX)对IRT引起的小鼠肠毒性缓解作用并不理想。发明人首次提出采用混合人肠道菌BGUSs活性(pooled human gut bacterialβ-glucuronidases,phBGUSs)筛选广谱强效抑制剂的策略。结果显示：DA加合物或其药学上可接受的盐作为β-葡萄糖醛酸苷酶抑制剂，在较低剂量即显示较强的体内抑制动物肠道BGUSs的作用，能有效缓解IRT在健康小鼠体内诱发的肠毒性，作用优于AMX。
在可选的实施方式中，桑属植物选自白桑，DA加合物由白桑的栓皮部位提取而得。
在可选的实施方式中，所述提取为醇提；可选地，所述醇提采用的萃取剂包括石油醚和乙酸乙酯中的至少一种，所述萃取剂优选为乙酸乙酯。
在可选的实施方式中，DA加合物包括：查耳酮与异戊二烯黄酮或异戊二烯黄酮醇的加合物或其衍生物，查耳酮与异戊二烯黄烷酮或异戊二烯黄烷醇的加合物、查耳酮与异戊二烯查耳酮的加合物、查耳酮与异戊二烯化2-芳基苯并呋喃的加合物或其衍生物、查耳酮与异戊二烯的加合物中的至少一种。
在可选的实施方式中，DA加合物包括表1所述化合物中的至少一种。
在可选的实施方式中，所述DA加合物包括下述化合物中的至少一种：所述Sanggenon G、所述Sanggenon C、所述Kuwanon L、所述Kuwanon G和所述Mulberrofuran G，更优选为Sanggenon G。
第二方面，本发明实施例还提供了如前述任意实施例所述的DA加合物在制备OATP2B1抑制剂中的应用。
第三方面，本发明实施例还提供了如前述任意实施例所述的DA加合物在制备治疗和/或预防去葡萄糖醛酸化产物在肠道积累从而导致的不良反应或疾病的药物中的应用，所述去葡萄糖醛酸化产物是由肠道菌GUS酶介导产生的。
DA加合物能够用于抑制催化去葡萄糖醛酸化的蛋白活性。
在可选的实施方式中，所述疾病包括药源性腹泻、非甾体类抗炎药相关性肠病和癌症。
在可选的实施方式中，所述药源性腹泻和/或非甾体类抗炎药相关性肠病为服用伊立替康、瑞戈非尼等抗癌药引起的腹泻、双氯芬酸钠、吲哚美辛、布洛芬和酮洛芬中的至少一种非甾体类抗炎药引起的肠病。
在可选的实施方式中，所述癌症为由肠道菌GUS酶介导的内源性成分和/或外源性成分的去葡萄糖醛酸化产物积累导致的癌症，所述内源性成分包括甾体激素类，胆红素，神经递质类如多巴胺、去甲肾上腺素、甲状腺素、血清素，胆汁酸，脂肪酸等中的至少一种；所述外源性成分包括杂环胺类(Heterocyclic Amines,HCAs)如PhIP、IQ、MelQx和3，8-diMelQx等，多环芳烃(Polycyclic Aromatic Hydrocarbons，PAHs)、酚类衍生物等中的至少一种。
在可选的实施方式中，所述内源性成分的去葡萄糖醛酸化产物积累导致的癌症包括乳腺癌、前列腺癌和甲状腺癌中的至少一种，外源性成分的去葡萄糖醛酸化产物积累导致的癌症包括结直肠癌等。
在可选的实施方式中，所述药物包括：由活性成分加上药学上可接受的辅助性成分制备而成的制剂。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
从桑白皮提取物中分离、筛选高效广谱抑制人肠道菌BGUSs的化合物。
为筛选强效广谱人BGUSs抑制剂，我们先采用分子对接分析，用三种代表性的纯化GUS蛋白EcoGUS、SpasGUS和SagaGUS预测桑白皮中特征性DA加合物成分对BGUSs的抑制作用，发现该桑属植物中不同类别的DA加合物对三种GUS蛋白均呈现较高的亲和力(表2，表2中化合物的结构式参见表1)。
进而以phBGUSs水解非特异底物4-硝基苯基-β-D-吡喃葡萄糖苷(PNPG)活性来指导桑白皮提取物中活性组分/成分的分离(图1)。桑白皮的醇提物(MSE)在30μg/mL即对phBGUSs活性产生较强抑制(>50％，图2)，对MSE分别用石油醚(PE)和乙酸乙酯(EA)萃取，发现EA萃取物(30μg/mL)能显著抑制phBGUSs的水解活性(>80％抑制，图1)，因此将EA萃取物进一步用正相硅胶柱层析分离，用PE：EA(5:1至1:4，V/V，各4L)、EA(4L)、甲醇(5L)依次洗脱，每500mL收集洗脱液，根据TLC点板结果合并相似组分，共得到12个流份(F1-12)，其中五个(F8-12)对phBGUSs的抑制>80％(图2)；再采用sephadex LH-20分离、制备液相(Pre-HPLC)纯化，获得多个单体化合物(表3)。通过MS二级图谱和NMR氢谱和碳谱分析，确定其均为DA加合物。
表1桑属植物中DA加合物
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表2桑属植物中DA加合物与三种肠道菌GUS蛋白的分子对接分析
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表3-中药桑白皮中分离得到的DA加合物成分及对混合人肠道菌总蛋白BGUSs活性的抑制作用
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SGG强效抑制phBUGs和纯化GUS酶的活性。
以EcoGUS筛选得到的的抑制剂阿莫沙平(AMX)为对照，我们进一步评估了SGG对BGUSs的抑制作用。SGG对phBGUSs水解PNPG活性表现出中等抑制作用(IC50 19.22μM)，而对照AMX基本不抑制(<20％，100μM)phBGUSs的水解活性(图2A，表4)。
表4-桑根酮G(SGG)和阿莫沙平(AMX)对人肠道菌总蛋白和纯化菌GUS蛋白的抑制效率(n＝3)
此外，SGG对三个纯化GUS蛋白EcoGUS、SpasGUS和SagaGUS水解PNPG均能强效抑制，IC50值分别为0.16μM、0.46μM、0.64μM，远低于AMX(1.01μM、1.77μM、11.94μM)(表4)。通过Lineweaver-Burk作图发现(图2B)，SGG对EcoGUS、SpasGUS和SagaGUS抑制模式分别属于竞争性、混合型以及非竞争性，对应的Ki值分别为0.09μM、0.79μM和3.85μM(表4)，表明该化合物可以通过多种方式与GUS蛋白灵活互作。而AMX对三种GUS蛋白的Lineweaver-Burk图均呈现平行线，表明AMX通过非竞争性抑制机制阻断三个蛋白的活性，Ki值分别为0.33μM、0.36μM和11.00μM(图2C，表4)。
采用分子对接分析探究SGG抑制BGUSs的分子机制，发现SGG与3个GUS蛋白形成复合物所需的结合能均远小于AMX，其中与EcoGUS结合能最低(-9.74kcal/mol)，与SagaGUS结合能最高(-7.18kcal/mol)，与其体外抑制效率一致(表5)。
表5-桑根酮G(SGG)和阿莫沙平(AMX)对肠道菌β-葡萄糖醛酸苷酶的结合自由能(S)和均方根误差(RMSD)值
图3显示，SGG与EcoGUS的多个氨基酸残基包括Glu504(EcoGUS的关键催化基团)分别形成氢键作用、与Phe448形成更强的pi-H互作，与SpasGUS的互作则主要通过与菌特异的环状结构(Gly362-Ile384)的Ala368和His364形成氢键和pi-H作用。而SGG不能完全占据SagaGUS的活性口袋，其侧链暴露在溶剂中，仅与SagaGUS的Phe523和Phe181分别形成氢键和pi-H互作。与SGG相比，AMX分子量小，能够完全占据GUS蛋白的活性口袋(图3)，主要与活性结构区域的催化残基谷氨酸残基结合，但所需结合能量较SGG高，因此不易与蛋白进行结合。
SGG抑制小鼠肠道内BGUSs活性。
进一步采用荧光成像技术，口服给予小鼠BGUSs荧光探针荧光素二-β-D-葡糖苷酸(FDGlcU)，考察SGG在整体动物水平对肠道内BGUSs活性的抑制作用(图4)。发现每天两次、连续三天口服给予SGG(0.4、1.0、2.5mg/kg)或AMX(1.0、5.0mg/kg)后，口服FDGlcU，通过IVIS Lumina XR体内成像系统(Caliper life Sciences)，检测小鼠肠道的荧光信号(激发光460nm，发射光520nm)，发现SGG中及高剂量(即每天1.0及2.5mg/kg)能显著降低小鼠肠内的荧光信号，且中、高剂量效果相当，表明每日口服1mg/kg SGG预处理可有效抑制小鼠肠道BGUSs活性。而AMX的两个受试剂量均对小鼠肠道微生物水解FDGlcU活性没有显著影响。
SGG缓解伊立替康对小鼠造成的腹泻。
进一步在健康小鼠体内观察SGG对IRT引起的胃肠道不良反应的影响(图5)。发现高剂量SGG(1mg/kg/day,每天两次)预处理，可明显减缓腹腔注射IRT引起的体重降低(图5A)，延迟小鼠死亡，显著提升小鼠生存率(图5B)，有效降低腹泻的严重程度(图5C)，其对生存率和腹泻的缓解作用优于AMX。腹腔注射IRT导致空肠顶部绒毛完全消失、隐窝丢失以及广泛的粘膜损伤，结肠腺体结构被破坏，空肠损伤比结肠损伤更为严重；高剂量SGG明显保护小鼠免受空肠和结肠上皮损伤，肠绒毛和腺体结构正常、上皮层完整，而AMX预处理仅对空肠显示出一定的保护，结肠中仍见炎症细胞浸润(图5D、5E)。
高剂量SGG预处理显著降低肠道菌BGUSs活性，导致实验期(day0-day9)小鼠粪便菌BGUSs活性持续降低并在后期维持在较低水平，而AMX预处理组第6天粪便菌BGUSs活性降低，但在第9天回升(图6A)。相应地，检测肠道组织中SN-38的蓄积发现，SN-38在十二指肠中积累量最高，其次是空肠和回肠，在结肠中的累积量比在小肠中低几个数量级；高剂量SGG预处理显著减少SN-38在不同小肠段及结肠的蓄积，而低剂量SGG或AMX预处理对此无显著影响(图6B、6C)，提示肠道组织中SN-38的蓄积与肠道损伤程度以及BGUS抑制剂的表现呈现很好的关联。此外，对空肠组织催化SN-38葡萄糖醛酸化的活性进行分析，发现高剂量SGG或AMX预处理可以阻断IRT对SN-38葡萄糖醛酸化活性的显著降低，而将其活性维持在正常水平(图6D)。对空肠组织的OATP2B1蛋白表达水平的分析结果也显示，IRT组小鼠的OATP2B1表达没有显著变化，高剂量SGG预处理显著降低了OATP2B1表达，低剂量SGG或AMX预处理对此则没有显著影响(图6E、6F)；体外检测人肠上皮Caco-2细胞对SN-38的摄取也证实SGG能有效抑制Caco-2细胞摄取SN-38，其IC50值为4μM，在30μM时达到最大抑制率约为60％，而AMX在低浓度(0.01和0.1μM)反而增强GUS活性(相对活性～140％)，在测试的最大浓度(30μM)对SN-38的摄取基本无影响(图6G)。
SGG对细菌生长的影响以及对人和菌GUS酶的选择性。
SGG和AMX在100μM对E.coli BL21(DE3)细胞的生长均无显著抑制(图7A)。此外，比较SGG对代表性纯化BGUSs蛋白和人GUS蛋白(hGUS)的影响，发现SGG抑制hGUS的IC50值为42.85μM，是其抑制phBGUSs的IC50的两倍，65～270倍于对三种纯化GUSs的IC50(图7B，表2)，表明SGG对微生物来源的GUS酶具有更高抑制倾向。
综上，本发明实施例提供来源于桑属植物的DA加合物具有靶向抑制肠道菌BGUSs活性，是抑制某些致癌原的过度激活导致的肿瘤风险、阻断药物肠肝循环并缓解相关药物的不良反应的新策略。而BGUSs本身结构和功能的复杂性亟需发展强效广谱抑制剂以满足临床需求。本发明实施例采用混合人粪菌总蛋白BGUS活性抑制策略，从中药桑白皮提取物中分离筛选一系列DA加合物类成分，其中代表性化合物SGG证实在体内有效缓解伊立替康引起的小鼠肠毒性，其不仅在体外、体内模型上显示强效广谱的BGUSs抑制特点，还能够抑制肠上皮细胞对SN-38的摄取。这种对SN-38肠道再激活(BGUSs抑制)和重新摄取(OATP2B1抑制)双重抑制的作用特点使其较以单一GUS蛋白筛选的抑制剂具有更大的优越性和临床应用潜力。
以上仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (2)
1.DA加合物在制备治疗和/或预防去葡萄糖醛酸化产物在肠道积累从而导致的不良反应的药物中的应用，其特征在于，所述DA加合物为：
、/>或/>；
所述去葡萄糖醛酸化产物是由肠道菌GUS酶介导产生的；
所述不良反应为药源性腹泻，所述药源性腹泻为服用伊立替康引起的腹泻。
2.根据权利要求1所述的应用，其特征在于，所述药物为：所述DA加合物加上药学上可接受的辅助性成分制备而成的各种制剂。
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