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

• 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
• 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

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.

拟议的研究的总体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，器官血流的模型，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 将显式膜隔室纳入预测模型，我们在深入评估了 各种膜几何形状和相关因素对细胞内浓度预测的影响。我们是 现在使用渗透率和分区的基本原理来构建PBPK的新框架 型号。这将使我们能够合并渗透率有限的分布，分区，器官血流和 具有显式膜动力学（MEMPBPK）的PBPK模型的主动运输。这个新的范式将 明显更好地预测细胞内浓度，并将满足未满足的关键需求 通过为人类的药物处置提供新颖的预测工具，具有成本效益的药物开发。 提出了三个具体目标。 1）新型生物物理方法将用于研究 药物渗透性和分配。具体而言，新型细胞显微镜技术将用于评估 细胞分布和进行单层细胞渗透率研究的时间顺序，一系列 将评估在当前资金期间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）开发一个新框架 PBPK和混合隔室PBPK模型，这些模型包含膜分配，渗透率限制 扩散和器官血流（MEMPBPK）。组件包括特定器官特定模型，用于混合动力和 完整的PBPK方法和使用我们已发表的对流扩散反应方法吸收的模型。 这些模型将用于AIM 3，以结合积极的吸收/外排传输和代谢来预测 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是 用于扩展和验证模型，以预测细胞内药物浓度的时间过程。 我们将着重于建模药物在肝脏中的处置和吸收药物 在转运蛋白和药物代谢酶的存在下胃肠道。