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

Predicting intracellular drug concentrations in the presence of transporters

预测转运蛋白存在下的细胞内药物浓度

基本信息

批准号：
9595707
负责人：
Kenneth Ray Korzekwa
金额：
$ 34.42万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9595707
关键词：
Active Biological Transport Address Adipocytes Apical Blood flow Cell Membrane Permeability Cells Childhood Clinical Clinical Data Convection Data Diffusion Dose Drug Interactions Drug Kinetics Enzymes Funding Gastrointestinal Agents Gastrointestinal tract structure Gender Geometry Goals Hepatic Human Hybrids In Situ In Vitro Intestinal Absorption Intestines Kinetics Lipids Liver Measurement Membrane Metabolism Methodology Microscopy Modeling Organ Organelles Permeability Pharmaceutical Preparations Phospholipids Physiological Publishing Rattus Reaction Research Research Infrastructure Safety Side Site Techniques Time Tissues absorption base biophysical properties biophysical techniques bosentan cost effective design dosage drug development drug efficacy extracellular first-in-human improved in vivo membrane model monolayer named group novel pharmacokinetic model predictive modeling predictive tools sound uptake

项目摘要

The overarching goal of the proposed research is to predict the intracellular and extracellular concentration- time profiles using models that include membrane partitioning, membrane permeability, organ blood flow, active transport, and metabolism. In the funding period from 2013-2016, we have made significant progress in incorporating explicit membrane compartments into predictive models, and we have evaluated in depth the impact of various membrane geometries and related factors on intracellular concentration prediction. We are now using the basic principles underlying permeability and partitioning to build a new framework for PBPK models. This will allow us to incorporate permeability-limited distribution, partitioning, organ blood flow, and active transport into PBPK models with explicit membrane kinetics (memPBPK). This new paradigm will provide markedly better predictions of intracellular concentrations, and will address an unmet critical need for cost effective drug development by providing novel predictive tools for drug disposition in humans. Three specific aims are proposed. 1) Novel biophysical methods will be used to study the cellular kinetics of drug permeability and partitioning. Specifically, novel cell microscopy techniques will be used to evaluate the time-course of cellular distribution and conduct cellular permeability studies in monolayers, and a range of explicit membrane models developed during the current funding period will be evaluated for their ability to quantify the observed membrane, organelle, and cellular distribution kinetics. 2) Develop a new framework for PBPK and hybrid compartmental-PBPK models that incorporate membrane partitioning, permeability-limited diffusion, and organ blood flow (memPBPK). Components include organ-specific models for use in hybrid and full PBPK approaches, and models for absorption using our published convection-diffusion-reaction approach. These models will be used in Aim 3 to incorporate active uptake/efflux transport and metabolism to predict intra- and extracellular concentration-time profiles. 3) In vivo experimental data from rats and humans will be used to expand and validate models to predict the time course of intra- and extracellular drug concentrations. We will focus on modeling the disposition of drugs in the liver and the absorption of drugs from the gastrointestinal tract in the presence of transporters and drug metabolizing enzymes.

拟议研究的首要目标是预测细胞内和细胞外浓度- 使用包括膜分配，膜渗透性，器官血流，主动运输和新陈代谢。在2013-2016年的资助期内，我们在以下方面取得了重大进展：将明确的膜隔室纳入预测模型，我们已经深入评估了各种膜几何形状和相关因素对细胞内浓度预测的影响。我们现在使用渗透性和分区的基本原理来构建PBPK的新框架模型这将使我们能够将渗透性限制的分布、分配、器官血流和主动转运到具有显式膜动力学的PBPK模型（memPBPK）中。这一新模式将提供细胞内浓度的明显更好的预测，并将解决未满足的关键需求，通过为药物在人体中的分布提供新的预测工具，实现成本有效的药物开发。提出了三个具体目标。1)新的生物物理学方法将被用于研究细胞动力学，药物渗透和分配。具体而言，将使用新的细胞显微镜技术来评估细胞分布的时间过程，并在单层中进行细胞渗透性研究，以及一系列将评估在当前资助期内开发的明确膜模型的能力，量化观察到的膜、细胞器和细胞分布动力学。2)制定新的框架， PBPK和混合隔室-PBPK模型，包括膜分配、渗透性限制扩散和器官血流量（memPBPK）。组件包括用于混合和完整的PBPK方法，以及使用我们发表的对流-扩散-反应方法的吸收模型。这些模型将用于目标3，以纳入主动摄取/外排转运和代谢，细胞内和细胞外浓度-时间曲线。3)来自大鼠和人类的体内实验数据将在用于扩展和验证模型，以预测细胞内和细胞外药物浓度的时间过程。我们将集中于模拟药物在肝脏中的分布和药物从肝脏的吸收。在转运蛋白和药物代谢酶的存在下，胃肠道。