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：
Seyoum Ayehunie
金额：
$ 21.83万
依托单位：
MATTEK CORPORATION
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

来源：
https://reporter.nih.gov/project-details/8714269
关键词：
Active Biological Transport Adsorption Animals Biological Availability Blinded Caco-2 Cells Carrier Proteins Cell Culture Techniques Cell Line Cells Characteristics Clinical Collagen Colon Data Development Diffusion Drops Drug Administration Routes Drug Delivery Systems Drug Industry Drug Interactions Drug Kinetics Drug Transport Drug toxicity Economic Factors Electrical Resistance Enzymes Epithelial Cells Epithelium Fibroblasts Gastrointestinal tract structure Gel Goals Hormones Human In Vitro Industry Interagency Coordinating Committee on the Validation of Alternative Methods Intestinal Absorption Intestinal Diseases Intestines Ion Transport Laboratories Lamina Propria Lead Liquid substance Malignant Neoplasms Membrane Metabolic Metabolism Methods Modeling Mucous body substance Multi-Drug Resistance Oral Oral Administration Organ P-Glycoprotein Patients Performance Permeability Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Preclinical Drug Evaluation Probability Process Property Proteins Reproducibility Research Safety Small Intestines Staging Structure Testing Therapeutic Thick Tissue Model Tissues Validation Variant Villus Work absorption base carrier mediated transport cost effective cytokine drug candidate drug development drug market enzyme activity glycosylation high throughput screening human ABCG2 protein human data human tissue improved in vitro Model in vivo inhibitor/antagonist interest intestinal villi kidney cell novel pre-clinical public health relevance small molecule success tool validation studies

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（由申请人提供）：药物管理的周期途径仍然是最方便的临床治疗方式，并且受到患者的优先选择，但是，良好的生物利用度是新候选疗法的必要特征。确定口服生物利用度的关键参数是跨小肠（SI）的药物运输和渗透性上皮。因此，准确预测候选药物体内人类运输/渗透性的SI上皮的体外模型对制药行业具有很高的兴趣。当前可用的体外模型具有明显的缺陷，可限制其在DRU开发应用中的效用，包括与体内载体介导的运输和细胞渗透的相关性不佳，以及缺乏体内人类小肠代谢酶的活性。当前的建议旨在开发用于药物开发应用中的体外人类SI。 SI模型将由原代人Si上皮细胞和在微多膜上培养的成纤维细胞支持，以产生具有体内类似人类药物运输和渗透性特征的差异分化的Si组织。由于该模型是由原发性正常（非癌）SI细胞产生的，因此与基于动物或癌症衍生的细胞系相比，该组织有望提供较高的性能。重大的初步结果表明，该目标很容易实现。该项目的目的包括优化培养参数，药物转运蛋白的表征和代谢酶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的渗透研究。将研究通过被动扩散和主动转运的药物渗透以及转运蛋白抑制剂的作用。在以下方面的渗透/吸收之间的比较：第2阶段的工作将包括对96孔，高通量筛选格式的进一步优化，将体外方法转移到其他实验室，以及在多个实验室中进行盲目验证研究的性能。结果将提交美国机构间协调替代方法验证委员会（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。精确，成本效益和可再现的体外手段的可用性将增强药物选择过程，并提高新药候选者临床成功的可能性。这款小说的体外工具将在整个制药行业中找到意义上的商业认可。

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）

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：
Pharmaceutical research
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

Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

DOI：
10.1016/j.ejpb.2015.03.002
发表时间：
2015-09
期刊：
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
影响因子：
0
作者：
Maschmeyer I;Hasenberg T;Jaenicke A;Lindner M;Lorenz AK;Zech J;Garbe LA;Sonntag F;Hayden P;Ayehunie S;Lauster R;Marx U;Materne EM
通讯作者：
Materne EM