An In Vitro Human Small Intestine Tissue Model for Drug Permeation Studies

用于药物渗透研究的体外人体小肠组织模型

基本信息

  • 批准号:
    8714269
  • 负责人:
  • 金额:
    $ 21.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The perioral route for drug administration remains the most convenient way of clinical therapy and is preferred by patients, however, good bioavailability is a necessary characteristic of new candidate therapeutics. A key parameter for determining oral bioavailability is drug transport and permeability across the small intestine (SI) epithelium. Therefore, in vitro models of SI epithelium that accurately predict in vivo human transport/permeability of candidate drugs are of high interest to the pharmaceutical industry. Currently available in vitro models have significant deficiencies which limit their utility for dru development applications, including poor correlation to in vivo human carrier-mediated transport and par cellular permeation, as well as a lack of in vivo human small intestine metabolic enzyme activity. The current proposal aims to develop an in vitro human SI for use in pharmaceutical development applications. The SI model will consist of primary human SI epithelial cells and fibroblasts cultured on micro porous membrane supports to produce well-differentiated SI tissues with in vivo-like human drug transport and permeability characteristics. Because the model is produced from primary normal (non-cancerous) SI cells, the tissue is expected to provide superior performance compared to currently available models based on animal or cancer-derived cell lines. Significant preliminary results indicate that this goal is readily attainable. Aims of the project include optimization of culture parameters, characterization of drug transporters and metabolizing enzymes, and permeation studies using a number of substrates that have been previously studied using the industry standard model, Caco-2 cells. Drug permeation via passive diffusion and active transport, along with the effect of transporter inhibitors, will be studied. A comparison between the permeation/absorption in: a) the SI model vs. human and b) Caco-2 cells vs. human will be made to determine if the SI model offers improved pharmacokinetic predictions versus the Caco-2 model. Phase 2 works will include further optimization of the SI tissue model to a 96-well, high-throughput screening format, transfer of the in vitro method to other laboratories, and performance of a blinded validation study in multiple laboratories. Results will be submitted to the US Interagency Coordinating Committee on Validation of Alternative Methods (ICCVAM) for review and validation. In addition, the effect of alternative donors and various pathological conditions on SI permeation will be investigated. The availability of an accurate, cost-effective, and reproducible in vitro means of assessing SI drug absorption will enhance the drug selection process and improve the probability of clinical success of new drug candidates. This novel, in vitro tool will find signifiant commercial acceptance throughout the pharmaceutical industry.
描述(申请人提供):经口给药途径仍然是临床治疗的最方便方式,也是患者的首选,然而,良好的生物利用度是新候选治疗剂的必要特征。确定口服生物利用度的关键参数是药物在小肠中的转运和渗透性(SI) 上皮因此,准确预测候选药物的体内人体转运/渗透性的SI上皮的体外模型是制药工业的高度兴趣。目前可用的体外模型具有显著的缺陷,这限制了它们在药物开发应用中的效用,包括与体内人载体介导的转运和par细胞渗透的相关性差,以及缺乏体内人小肠代谢酶活性。目前的提案旨在开发一种用于药物开发应用的体外人SI。 SI模型将由在微孔膜支持物上培养的原代人SI上皮细胞和成纤维细胞组成,以产生具有体内样人药物转运和渗透性特征的分化良好的SI组织。因为该模型是由原代正常(非癌性)SI细胞产生的,所以与目前基于动物或癌症来源的细胞系的可用模型相比,预期该组织提供上级性能。重要的初步结果表明,这一目标是容易实现的。该项目的目的包括优化培养参数,药物转运蛋白和代谢酶的表征,以及使用先前使用行业标准模型Caco-2细胞研究的许多底物进行渗透研究。将研究通过被动扩散和主动转运的药物渗透,沿着转运蛋白抑制剂的作用。将比较以下模型的渗透/吸收:a)SI模型与人和B)Caco-2细胞与人,以确定SI模型是否提供了与Caco-2模型相比更好的药代动力学预测。 第2阶段的工作将包括进一步优化SI组织模型,使其成为96孔高通量筛选格式,将体外方法转移到其他实验室,以及在多个实验室进行盲态验证研究。结果将提交给美国替代方法验证机构间协调委员会(ICCVAM)进行审查和验证。此外,将研究替代供体和各种病理条件对SI渗透的影响。一个准确的,具有成本效益的,和可重复的体外方法评估SI药物吸收的可用性将加强药物选择过程,提高新药候选人的临床成功的概率。这种新颖的体外工具将在整个制药行业获得重要的商业认可。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.
Human Primary Cell-Based Organotypic Microtissues for Modeling Small Intestinal Drug Absorption.
  • DOI:
    10.1007/s11095-018-2362-0
  • 发表时间:
    2018-02-23
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Ayehunie S;Landry T;Stevens Z;Armento A;Hayden P;Klausner M
  • 通讯作者:
    Klausner M
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Seyoum Ayehunie其他文献

Seyoum Ayehunie的其他文献

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{{ truncateString('Seyoum Ayehunie', 18)}}的其他基金

Organotypic Culture Models (OCM) developed from experimental animals for Chemical Toxicity Screening.
器官培养模型 (OCM) 由用于化学毒性筛选的实验动物开发而成。
  • 批准号:
    10079739
  • 财政年份:
    2020
  • 资助金额:
    $ 21.83万
  • 项目类别:
An In Vitro Human Small Intestine Tissue Model for Drug Permeation Studies
用于药物渗透研究的体外人体小肠组织模型
  • 批准号:
    9210635
  • 财政年份:
    2014
  • 资助金额:
    $ 21.83万
  • 项目类别:
An In Vitro Human Small Intestine Tissue Model for Drug Permeation Studies
用于药物渗透研究的体外人体小肠组织模型
  • 批准号:
    9049151
  • 财政年份:
    2014
  • 资助金额:
    $ 21.83万
  • 项目类别:
Use of a CB2 Ligand to prevent HIV-1 Infection and Transmission
使用 CB2 配体预防 HIV-1 感染和传播
  • 批准号:
    8602723
  • 财政年份:
    2013
  • 资助金额:
    $ 21.83万
  • 项目类别:
Use of a CB2 Ligand to prevent HIV-1 Infection and Transmission
使用 CB2 配体预防 HIV-1 感染和传播
  • 批准号:
    8681359
  • 财政年份:
    2013
  • 资助金额:
    $ 21.83万
  • 项目类别:
In Vitro Human Tissue Model for Intravaginal Drug Delivery
用于阴道内药物输送的体外人体组织模型
  • 批准号:
    7910090
  • 财政年份:
    2010
  • 资助金额:
    $ 21.83万
  • 项目类别:
Validation of a Human In Vitro Vaginal Irritation Test
人体体外阴道刺激试验的验证
  • 批准号:
    7220081
  • 财政年份:
    2007
  • 资助金额:
    $ 21.83万
  • 项目类别:
Validation of Human Vaginal Tissue Assay for Endocrine Disruptors
人体阴道组织内分泌干扰物检测的验证
  • 批准号:
    8207929
  • 财政年份:
    2007
  • 资助金额:
    $ 21.83万
  • 项目类别:
Validation of a Human In Vitro Vaginal Irritation Test
人体体外阴道刺激试验的验证
  • 批准号:
    7937022
  • 财政年份:
    2007
  • 资助金额:
    $ 21.83万
  • 项目类别:
Validation of Organotypic Vaginal Tissue Based Assay for Endocrine Disruptors
基于器官型阴道组织的内分泌干扰物测定的验证
  • 批准号:
    7270190
  • 财政年份:
    2007
  • 资助金额:
    $ 21.83万
  • 项目类别:

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