权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9049151
负责人：
Seyoum Ayehunie
金额：
$ 64.88万
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/9049151
关键词：
ABCG2 gene Affect Animal Model Animals 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 Transport 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 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 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 overexpression pre-clinical protein expression 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.