P-糖蛋白与药物相互作用模型的建立及其在药物评价中的应用
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摘要
P-糖蛋白(P-gp)与药物相互作用研究属于药物研发早期药代性质预测的重要组成部分。新药的研发过程中,随着组合化学的发展,诞生了数量庞大的组合化学分子库,成千上万的新化学实体(NCEs)需要高通量、快速、灵敏而有效的评价筛选方法。本研究旨在建立快速预测P-gp与药物相互作用的体外及在体评价模型,丰富和完善临床前创新化合物药代性质评价体系,为创新药物的高内涵筛选提供技术支撑。
课题研究内容分为两大部分:首先建立体外Caco-2细胞、肠外翻及在体肠灌流等模型,并采用多种工具药物对模型进行验证,以确保模型可靠性和实用性。所建成的模型可用于药物的肠道吸收性质预测;评价药物是否为P-gp底物、抑制剂及诱导剂等。其次应用所建立的模型和方法,开展对多种类型的创新化合物和适宜的中药复方与P-gp的相互作用进行预测和评价。
模型建立及评价:
Caco-2单层细胞外排模型,利用Caco-2细胞类似小肠上皮细胞且高表达P-gp的特性,将细胞接种到Millicell小室膜上,待细胞分化完成后进行转运实验,实验时分别将药物加入顶侧(AP侧)或底侧(BL侧),不同时间点取对应侧的样品,采用LC-MS或LC-MS/MS检测其药物浓度变化,计算表观渗透系数,可根据研究目的的不同,用于评价P-gp底物或抑制剂。
荧光法预测P-gp抑制剂模型,采用具有荧光性质的P-gp底物Calcein-AM或Rho123与待测药物共同孵育作用于Caco-2细胞,实验根据细胞内荧光强度的变化,评价待测化合物是否为P-gp抑制剂。该模型可采用单层细胞种植于96孔板,联合荧光分光光度计检测,可实现药物的高通量筛选;也可以采用细胞悬液,联合流式细胞仪,可极大的提高检测准确性,适用于药物研发不同阶段的筛选。
多药耐药逆转模型,P-gp是导致抗肿瘤药物产生MDR主要因素之一。通过考察肿瘤细胞(本实验采用Caco-2细胞)在P-gp抑制剂作用引起抗肿瘤药物IC50变化,用于抗肿瘤药物多药耐药逆转剂和P-gp抑制剂的快速筛查。
P-gp体外诱导模型,采用Western blot法,将药物与Caco-2细胞共同孵育特定时间后,通过膜蛋白中的P-gp表达量的变化,评价药物对P-gp的诱导作用。
建立了大鼠肠外翻模型,除用于P-gp的底物及抑制剂的评价外,还可用于考察和比较药物在不同肠段的吸收差异。为更加真实的模拟药物小肠吸收过程,建立大鼠在体肠灌流模型,模拟小肠对药物的吸收,用于评价P-gp的底物及抑制剂。
模型应用:
采用Caco-2单层细胞外排模型,对LZN033及其系列结构修饰物(该系列40个化合物)进行了透膜吸收预测,实验提示该类化合物基团中取代基上的带正电原子被取代后的化合物稳定性显著增高,提示该位点的取代基能提高其抗酶解的能力;带正电原子的取代基上的氢被进行合适的取代后的化合物透膜性明显提高,提示该位点的基团能提高化合物的透膜性。其中033、502、504、505、511、523初步评价为P-gp底物,提示上述化合物在采取合用抑制剂的方法,可能会提高化合物的体内生物利用度。
对多种化合物的在Caco-2单层细胞上的双向转运特性进行初步评价,结果预测R-8021、S-8021、SFNF可能为P-gp和MRP2底物,Agm、SP-8、RS-8021、C36D2、HS-1等不受转运蛋白影响。初步解释了体内实验R-8021较RS-8021生物利用度低的原因,即R-8021受到P-gp外排的影响,导致进入体内的R-8021药量降低。上述各药由表观渗透系数Papp预测的体内生物利用度的结果,与体内实验基本相符。
采用荧光法模型对17种化合物进行筛选,结果表明LSY-001、LSY-002、LSY-003、LSY-004分别增加胞内Calcein含量18.4%、27.2%、18.5%和30.5%,研究结果表明上述化合物为P-gp抑制剂。
在对中药复方评价中,研究了当归芍药散在Caco-2细胞上的转运特性,针对中药复方成分复杂,且中药煎煮液质地浓稠,不适于直接给药的缺点,设计了经肠外翻给药后,将肠外翻内液用于细胞给药,实现了在细胞水平,中药复方经肠吸收有效成分的研究,结果表明复方滤过液和肠外翻内液中香草酸、白芍苷的Papp(A→B)高于各单体成分和单体成分混合液中Papp(A→B),提示在复方中药中存在其他配伍成分,产生药物相互作用,促进其A面到B面的药物转运,造成表观渗透系数的改变。而复方滤过液和肠外翻内液中Comp.A的Papp(A→B)低于单体和单体混合液中Papp(A→B),提示在复方中药中存在其他配伍成分抑制其由A面到B面的药物转运,造成透膜吸收性的改变。由此表明中药复方研究需从整体角度出发,单味中药成分或化学单体成分无法真实的反映中药复方的体内吸收特性。
综上所述,目前已在体外、在体和离体等层次上初步建立起早期药物代谢性质快速评价体系中化合物与P-gp相互作用研究模型,根据不同实验目的,包括化合物所处的不同研发阶段的要求,进行相应模型的选择或不同模型的组合,能够完成对化合物的肠道吸收特性进行快速评价;对转运蛋白中的P-gp的底物、抑制剂和诱导剂进行筛选,为药物设计和开发药物的体内吸收特性评价提供依据,并对体内多种转运蛋白的研究提供参考依据。
Drug-drug interactions with P-glycoprotein (P-gp) are known to play a significant role in early drug discovery. Combinatorial chemistry and other advances in synthetic chemistry have led to a tremendous inflow of new chemical entities (NCEs) being fed into the screens for high throughput, high efficiency and high accuracy.There are diverse screens including in vivo and in vitro that are set-up in order to predict the interactions between P-glycoprotein and compounds.
This dissertation consists of two parts. Firstly, we established Caco-2 cell line model, in vitro everted gut sacs and in situ perfusion method. A set of well-characterized and well-studied compounds were selected to test the validity of the assay.
Model Construction:
The Caco-2 cell monolayer is similar with the small intestine epithelium, which expresses P-gp highly and makes it an attractive model for P-gp substrate screening. In the transport experiment, the Caco-2 cells are seeded in the Millicell firstly, and 21 days later the cells complete the differentiation and can be used for transport studies. The bi-directional permeability studies were initiated by adding an appropriate volume of buffer containing test compound to either the apical (for apical to basolateral transport; A to B) or basolateral (for basolateral to apical transport; B to A) side of the monolayer. The concentrations of test compound were analyzed by LC-MS or LC-MS/MS method. Then apparent permeability (Papp) was calculated.
P-gp inhibition studies were conducted using fluorescent dye Rhodamine123 and Calcein-AM as the probe. Accumulation of intracellular calcein fluorescence was measured using a Spectrofluorophotometer or flow cytometry. P-gp inhibitors significantly increased intracellular calcein fluorescence in Caco-2 cells.
Using cultured Caco-2 monolayers on 96 well and measured with a Spectrofluorophotometer is a useful tool in high-throughput screening. Importantly, using Caco-2 cells in suspension combined with flow cytometry analysis improve reliability, specificity, and sensitivity of the assay.
We established multi-drug resistance reversal model for P-gp, which was one of major causes for multidrug resistance (MDR).The determination of inhibitory concentrations (IC50 values) allowed to differentiate cytostatics into P-gp or non-P-gp inhibitors.This assay was improved as a high-throughput screening-capable assay. P-gp induction model: induction of P-gp expression in Caco-2 cells treated with compounds was measured using Western blot analysis. Our results showed that this model couble be used to the research of P-gp induction.
The effects of compounds on rat intestinal P-gp function were studied on everted gut sacs and in situ intestinal perfusion models. The absorption of drugs were studied by the means of the everted gut scas and predict absorption trend in different intestines.
Model Application:
Permeability of two series new peptide drug candidates synthesized by our institute was evaluated in Caco-2 cell monolayer. Results from Caco-2 model demonstrated that if the N atom in free amino groups at N terminal ureido of the linear decapeptide substituted by alkyl group, the stability of the peptide increased signicantly. The H atom in free amino groups at N terminal ureido of the linear decapeptide substituted by alkyl group, the modified peptide shows high permeability.
We used Caco-2 cells to screen compounds for their permeability characteristics and P-glycoprotein interactions on Bi-directional transport method. Compounds such as R-8021, S-8021 and thiophenorphine were P-gp and MRP2 substrates,thus Agm, SP-8, RS-8021, C36D2 and HS-1 were not. This result explained lower bioavailability of R-8021 comparing to RS-8021.
Fluorescence assay was used to screen 17 componds’interaction with P-gp. It shows that LSY-001, LSY-002, LSY-003 and LSY-004 upregulated intracellular calcein up to 18.4%, 27.2%, 18.5% and 30.5% respectively. The result indicated that these four compounds were P-gp inhibitors.
The permeability characteristics of Traditional Chinese Medicine prescription Dang-gui Shao-yao San (DSS) were carried on Caco-2 cell monolayer. A new method was designed, in which the internal liquid obtained from everted gut sacs was added to Caco-2 cell incubation culture. By using this assay, it may overcome defects such as constituents complex and thick in Traditional Chinese Medicine prescription. The results indicated that Papp(A→B) of vanillic acid and albiflorin after compound filtering and the internal liquid obtained from everted gut sacs was significantly higher than that of the monomers or mixture of monomers in DSS. It shows that in the presence of other herb couple components, the influx permeability (A to B) of vanillic acid and albiflorin significantly increased promote transport. Otherwise, Compound A shows just the opposite result.
In summary, we had successfully established integated rapid Drug-drug interactions with P-glycoprotein models. It could be used to screen compounds associated with P-glycoprotein in vitro, in vivo and in situ. The screening models of discovery compounds for their intestinal permeability characteristics and P-glycoprotein interactions are well established and used in pharmaceutical industries. Furthermore identification of compounds that are P-gp substrates, inhibitors, and inducers can aid drug candidate selection and optimization and offer reference to the research of other transport proteins.
课题研究内容分为两大部分:首先建立体外Caco-2细胞、肠外翻及在体肠灌流等模型,并采用多种工具药物对模型进行验证,以确保模型可靠性和实用性。所建成的模型可用于药物的肠道吸收性质预测;评价药物是否为P-gp底物、抑制剂及诱导剂等。其次应用所建立的模型和方法,开展对多种类型的创新化合物和适宜的中药复方与P-gp的相互作用进行预测和评价。
模型建立及评价:
Caco-2单层细胞外排模型,利用Caco-2细胞类似小肠上皮细胞且高表达P-gp的特性,将细胞接种到Millicell小室膜上,待细胞分化完成后进行转运实验,实验时分别将药物加入顶侧(AP侧)或底侧(BL侧),不同时间点取对应侧的样品,采用LC-MS或LC-MS/MS检测其药物浓度变化,计算表观渗透系数,可根据研究目的的不同,用于评价P-gp底物或抑制剂。
荧光法预测P-gp抑制剂模型,采用具有荧光性质的P-gp底物Calcein-AM或Rho123与待测药物共同孵育作用于Caco-2细胞,实验根据细胞内荧光强度的变化,评价待测化合物是否为P-gp抑制剂。该模型可采用单层细胞种植于96孔板,联合荧光分光光度计检测,可实现药物的高通量筛选;也可以采用细胞悬液,联合流式细胞仪,可极大的提高检测准确性,适用于药物研发不同阶段的筛选。
多药耐药逆转模型,P-gp是导致抗肿瘤药物产生MDR主要因素之一。通过考察肿瘤细胞(本实验采用Caco-2细胞)在P-gp抑制剂作用引起抗肿瘤药物IC50变化,用于抗肿瘤药物多药耐药逆转剂和P-gp抑制剂的快速筛查。
P-gp体外诱导模型,采用Western blot法,将药物与Caco-2细胞共同孵育特定时间后,通过膜蛋白中的P-gp表达量的变化,评价药物对P-gp的诱导作用。
建立了大鼠肠外翻模型,除用于P-gp的底物及抑制剂的评价外,还可用于考察和比较药物在不同肠段的吸收差异。为更加真实的模拟药物小肠吸收过程,建立大鼠在体肠灌流模型,模拟小肠对药物的吸收,用于评价P-gp的底物及抑制剂。
模型应用:
采用Caco-2单层细胞外排模型,对LZN033及其系列结构修饰物(该系列40个化合物)进行了透膜吸收预测,实验提示该类化合物基团中取代基上的带正电原子被取代后的化合物稳定性显著增高,提示该位点的取代基能提高其抗酶解的能力;带正电原子的取代基上的氢被进行合适的取代后的化合物透膜性明显提高,提示该位点的基团能提高化合物的透膜性。其中033、502、504、505、511、523初步评价为P-gp底物,提示上述化合物在采取合用抑制剂的方法,可能会提高化合物的体内生物利用度。
对多种化合物的在Caco-2单层细胞上的双向转运特性进行初步评价,结果预测R-8021、S-8021、SFNF可能为P-gp和MRP2底物,Agm、SP-8、RS-8021、C36D2、HS-1等不受转运蛋白影响。初步解释了体内实验R-8021较RS-8021生物利用度低的原因,即R-8021受到P-gp外排的影响,导致进入体内的R-8021药量降低。上述各药由表观渗透系数Papp预测的体内生物利用度的结果,与体内实验基本相符。
采用荧光法模型对17种化合物进行筛选,结果表明LSY-001、LSY-002、LSY-003、LSY-004分别增加胞内Calcein含量18.4%、27.2%、18.5%和30.5%,研究结果表明上述化合物为P-gp抑制剂。
在对中药复方评价中,研究了当归芍药散在Caco-2细胞上的转运特性,针对中药复方成分复杂,且中药煎煮液质地浓稠,不适于直接给药的缺点,设计了经肠外翻给药后,将肠外翻内液用于细胞给药,实现了在细胞水平,中药复方经肠吸收有效成分的研究,结果表明复方滤过液和肠外翻内液中香草酸、白芍苷的Papp(A→B)高于各单体成分和单体成分混合液中Papp(A→B),提示在复方中药中存在其他配伍成分,产生药物相互作用,促进其A面到B面的药物转运,造成表观渗透系数的改变。而复方滤过液和肠外翻内液中Comp.A的Papp(A→B)低于单体和单体混合液中Papp(A→B),提示在复方中药中存在其他配伍成分抑制其由A面到B面的药物转运,造成透膜吸收性的改变。由此表明中药复方研究需从整体角度出发,单味中药成分或化学单体成分无法真实的反映中药复方的体内吸收特性。
综上所述,目前已在体外、在体和离体等层次上初步建立起早期药物代谢性质快速评价体系中化合物与P-gp相互作用研究模型,根据不同实验目的,包括化合物所处的不同研发阶段的要求,进行相应模型的选择或不同模型的组合,能够完成对化合物的肠道吸收特性进行快速评价;对转运蛋白中的P-gp的底物、抑制剂和诱导剂进行筛选,为药物设计和开发药物的体内吸收特性评价提供依据,并对体内多种转运蛋白的研究提供参考依据。
Drug-drug interactions with P-glycoprotein (P-gp) are known to play a significant role in early drug discovery. Combinatorial chemistry and other advances in synthetic chemistry have led to a tremendous inflow of new chemical entities (NCEs) being fed into the screens for high throughput, high efficiency and high accuracy.There are diverse screens including in vivo and in vitro that are set-up in order to predict the interactions between P-glycoprotein and compounds.
This dissertation consists of two parts. Firstly, we established Caco-2 cell line model, in vitro everted gut sacs and in situ perfusion method. A set of well-characterized and well-studied compounds were selected to test the validity of the assay.
Model Construction:
The Caco-2 cell monolayer is similar with the small intestine epithelium, which expresses P-gp highly and makes it an attractive model for P-gp substrate screening. In the transport experiment, the Caco-2 cells are seeded in the Millicell firstly, and 21 days later the cells complete the differentiation and can be used for transport studies. The bi-directional permeability studies were initiated by adding an appropriate volume of buffer containing test compound to either the apical (for apical to basolateral transport; A to B) or basolateral (for basolateral to apical transport; B to A) side of the monolayer. The concentrations of test compound were analyzed by LC-MS or LC-MS/MS method. Then apparent permeability (Papp) was calculated.
P-gp inhibition studies were conducted using fluorescent dye Rhodamine123 and Calcein-AM as the probe. Accumulation of intracellular calcein fluorescence was measured using a Spectrofluorophotometer or flow cytometry. P-gp inhibitors significantly increased intracellular calcein fluorescence in Caco-2 cells.
Using cultured Caco-2 monolayers on 96 well and measured with a Spectrofluorophotometer is a useful tool in high-throughput screening. Importantly, using Caco-2 cells in suspension combined with flow cytometry analysis improve reliability, specificity, and sensitivity of the assay.
We established multi-drug resistance reversal model for P-gp, which was one of major causes for multidrug resistance (MDR).The determination of inhibitory concentrations (IC50 values) allowed to differentiate cytostatics into P-gp or non-P-gp inhibitors.This assay was improved as a high-throughput screening-capable assay. P-gp induction model: induction of P-gp expression in Caco-2 cells treated with compounds was measured using Western blot analysis. Our results showed that this model couble be used to the research of P-gp induction.
The effects of compounds on rat intestinal P-gp function were studied on everted gut sacs and in situ intestinal perfusion models. The absorption of drugs were studied by the means of the everted gut scas and predict absorption trend in different intestines.
Model Application:
Permeability of two series new peptide drug candidates synthesized by our institute was evaluated in Caco-2 cell monolayer. Results from Caco-2 model demonstrated that if the N atom in free amino groups at N terminal ureido of the linear decapeptide substituted by alkyl group, the stability of the peptide increased signicantly. The H atom in free amino groups at N terminal ureido of the linear decapeptide substituted by alkyl group, the modified peptide shows high permeability.
We used Caco-2 cells to screen compounds for their permeability characteristics and P-glycoprotein interactions on Bi-directional transport method. Compounds such as R-8021, S-8021 and thiophenorphine were P-gp and MRP2 substrates,thus Agm, SP-8, RS-8021, C36D2 and HS-1 were not. This result explained lower bioavailability of R-8021 comparing to RS-8021.
Fluorescence assay was used to screen 17 componds’interaction with P-gp. It shows that LSY-001, LSY-002, LSY-003 and LSY-004 upregulated intracellular calcein up to 18.4%, 27.2%, 18.5% and 30.5% respectively. The result indicated that these four compounds were P-gp inhibitors.
The permeability characteristics of Traditional Chinese Medicine prescription Dang-gui Shao-yao San (DSS) were carried on Caco-2 cell monolayer. A new method was designed, in which the internal liquid obtained from everted gut sacs was added to Caco-2 cell incubation culture. By using this assay, it may overcome defects such as constituents complex and thick in Traditional Chinese Medicine prescription. The results indicated that Papp(A→B) of vanillic acid and albiflorin after compound filtering and the internal liquid obtained from everted gut sacs was significantly higher than that of the monomers or mixture of monomers in DSS. It shows that in the presence of other herb couple components, the influx permeability (A to B) of vanillic acid and albiflorin significantly increased promote transport. Otherwise, Compound A shows just the opposite result.
In summary, we had successfully established integated rapid Drug-drug interactions with P-glycoprotein models. It could be used to screen compounds associated with P-glycoprotein in vitro, in vivo and in situ. The screening models of discovery compounds for their intestinal permeability characteristics and P-glycoprotein interactions are well established and used in pharmaceutical industries. Furthermore identification of compounds that are P-gp substrates, inhibitors, and inducers can aid drug candidate selection and optimization and offer reference to the research of other transport proteins.
引文
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