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：
9210635
负责人：
Seyoum Ayehunie
金额：
$ 50.8万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210635
关键词：
ABCG2 gene Affect Animal Model Animals Biological Biological Assay Biological Availability C10 chemokine CCL2 gene CYP2C19 gene CYP2C9 gene CYP2D6 gene CYP3A4 gene CYP3A5 gene Caco-2 Cells Cancer cell line Carrier Proteins Cell Culture Techniques Cell Line Cells Characteristics Colon Consensus Cytochromes Data Development Drug Compounding Drug Costs Drug Formulations Drug Industry Drug Interactions Drug Kinetics Drug Modelings Economics Electrical Resistance Enzymes Epithelium Failure Formulation Gastrointestinal tract structure Goals Histology Hormones Human In Vitro Intestines Laboratories Letters Measures Metabolic Metabolism Methods Microsomes Modeling Multi-Drug Resistance Oral Organ Outcome P-Glycoprotein Permeability Pharmaceutical Preparations Phase Phosphoric Monoester Hydrolases Preclinical Drug Development Preclinical Drug Evaluation Property Reproducibility Research Resources Rodent Sensitivity and Specificity Small Intestines Standardization System Test Result Testing Time Tissue Donors Tissue Model Tissues Variant absorption base clinical efficacy cost cytokine design drug candidate drug clearance drug development drug market drug metabolism drug testing efflux pump enzyme activity esterase gastrointestinal human tissue improved in vitro Assay in vitro Model in vivo kidney cell novel therapeutics pre-clinical predictive modeling protein expression protein transport public health relevance response screening tool

项目摘要

DESCRIPTION (provided by applicant): Approximately 60% of currently marketed drugs are orally administered formulations whose clinical efficacy critically depends on the absorption from the small intestine (SMI). However, currently available in vitro intestinal models rely predominantly on cancer cell lines that do not recapitulate the 3D microenvironment of the small intestine. Likewise, animal models often fail short in predicting in vivo human outcomes of candidate drugs. During Phase I, we successfully developed a promising small intestine drug permeation model based on an in vitro, organotypic tissue comprised of human SMI cells. Characterization of the in vitro SMI tissues showed good correspondence to native human tissue in terms of histology, transepithelial electrical resistance, and structural features. The utility of the SMI model for drug permeation studies was demonstrated. In vitro SMI permeability data strongly correlated with in vivo human absorption data (r2 = 0.87 - 0.95) whereas data from the widely-used Caco-2 cell line model was less predictive (r2 = 0.81). Permeability data also demonstrated that efflux transporters were functional in the SMI in vitro tissue and inhibition studies showed that the SMI tissue will likely be useful to study drug-drug interactions. An economic analysis of the in vitro model showed significant advantages versus comparable rodent bioavailability studies. The ultimate goal of this project is produce a validated, biologically relevant organotypic SMI model that predicts intestinal drug absorption/bioavailability of orally administered drugs. The human in vivo-like characteristics of the SMI model and its capacity to measure drug absorption, metabolism, and drug-drug interactions make it a superior tool to existing in vitro and ex-vivo methods. In the proposed application, we will finalize a drug permeation and metabolism prediction model. Reproducibility of the model will be determined and transferability of the in vitro assay methods to other laboratories will be demonstrated. Successful completion of these Phase 2 goals will result in an extremely useful model for early preclinical drug screening. The human primary cell based SMI tissue model will improve pharmacokinetic analysis of new drug formulations, accelerate drug development, and reduce the ever- increasing development cost of drugs.

描述（由适用提供）：大约60％的当前销售药物是口服的配方，其临床效率在关键上取决于小肠（SMI）的吸收。但是，目前在体外肠模型中可用的主要依赖于不概括小肠3D微环境的癌细胞系。同样，动物模型通常在预测候选药物的体内人类预后失败。在第一阶段，我们成功地基于人类SMI细胞的体外有机组织建立了一个承诺的小肠药物渗透模型。体外SMI组织的表征在组织学，经层电阻和结构特征方面表现出与天然人体组织的良好对应关系。证明了SMI模型用于药物渗透研究的实用性。体外SMI渗透率数据与体内人体受苦数据密切相关（R2 = 0.87-0.95），而来自广泛使用的Caco-2细胞系模型的数据则较低（R2 = 0.81）。渗透率数据还表明，外排转运蛋白在SMI体外组织中起作用，并且抑制研究表明，SMI组织可能对研究药物 - 药物相互作用可能很有用。对体外模型的经济分析表明，具有显着优势与可比的啮齿动物生物利用度研究。该项目的最终目标是通过验证的，具有生物学相关的有机SMI模型的，该模型可以预测口服药物的肠道药物丧失/生物可涂性。 SMI模型的人体内样特征及其衡量药物丢失，代谢和药物相互作用的能力使其成为现有体外和前体内方法的卓越工具。在拟议的应用中，我们将最终确定药物渗透和代谢预测模型。将确定模型的可重复性，并将证明体外测定方法向其他实验室的可转移性。成功完成这些2阶段目标将为早期临床前药物筛查带来极为有用的模型。基于人类的基于细胞的SMI组织模型将改善对新药配方，加速药物开发以及降低药物不断增长的开发成本的药代动力学分析。