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
• 负责人: Seyoum Ayehunie
• 金额: $ 64.88万
• 依托单位: MATTEK CORPORATION
• 依托单位国家: 美国
• 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

 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（由申请人提供）：目前上市的药物中约有60%为口服制剂，其临床疗效主要取决于小肠（SMI）的吸收。然而，目前可用的体外肠模型主要依赖于不重现小肠3D微环境的癌细胞系。同样，动物模型在预测候选药物的体内人体结果方面往往失败。在第一阶段，我们成功地开发了一个有前途的小肠药物渗透模型的基础上，在体外，器官型组织组成的人SMI细胞。体外SMI组织的表征显示出在组织学、跨上皮电阻和结构特征方面与天然人体组织的良好对应性。SMI模型用于药物渗透研究的实用性得到了证明。体外SMI渗透性数据与体内人体吸收数据密切相关（r2 = 0.87 - 0.95），而广泛使用的Caco-2细胞系模型的数据预测性较低（r2 = 0.81）。渗透性数据还表明，外排转运蛋白在SMI体外组织中具有功能，抑制研究表明SMI组织可能有助于研究药物相互作用。体外模型的经济分析显示，与啮齿动物生物利用度研究相比，具有显著优势。 该项目的最终目标是产生一个有效的，生物学相关的器官型SMI模型，预测口服药物的肠道药物吸收/生物利用度。SMI模型的类人体内特征及其测量药物吸收、代谢和药物-药物相互作用的能力使其成为优于现有体外和离体方法的上级工具。在所提出的应用中，我们将最终确定药物渗透和代谢预测模型。将确定模型的重现性，并证明体外试验方法可转移至其他实验室。这些2期目标的成功完成将为早期临床前药物筛选提供一个非常有用的模型。基于人原代细胞的SMI组织模型将改善新药物制剂的药代动力学分析，加速药物开发，并降低不断增加的药物开发成本。